Cardiotoxicity of nano-particles

    Cardiotoxicity of nano-particles Hasan Badie Bostan, Ramin Rezaee, Mahmoud Gorji Valokala, Konstantinos Tsarouhas, Kirill Golokhvast, Aristidis M. Tsatsakis, Gholamreza Karimi PII: DOI: Reference:

S0024-3205(16)30574-4 doi:10.1016/j.lfs.2016.09.017 LFS 15027

To appear in:

Life Sciences

Received date: Revised date: Accepted date:

25 June 2016 14 September 2016 23 September 2016

Please cite this article as: Bostan Hasan Badie, Rezaee Ramin, Valokala Mahmoud Gorji, Tsarouhas Konstantinos, Golokhvast Kirill, Tsatsakis Aristidis M., Karimi Gholamreza, Cardiotoxicity of nano-particles, Life Sciences (2016), doi:10.1016/j.lfs.2016.09.017

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Cardiotoxicity of nano-particles

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Kirill Golokhvast4, Aristidis M. Tsatsakis5,*, Gholamreza Karimi1,*

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Hasan Badie Bostan1, Ramin Rezaee2,4, Mahmoud Gorji Valokala1, Konstantinos Tsarouhas3,

Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical

Department of Physiology and Pharmacology, School of Medicine, North Khorasan

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2

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Sciences, Mashhad, Iran

University of Medical Sciences, Bojnurd, Iran.

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Cardiology Clinic, General University Hospital of Larisa, Larisa, Greece Scientific Educational Center of Nanotechnology, Far Eastern Federal University, 10

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Pushkinskaya Street, Vladivostok 690950, Russia Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete,

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Heraklion 71003, Greece. *Corresponding authors: 

Gholamreza Karimi: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Tel.: +985138823255-66, Fax: +985138823255, E-mail address: [email protected]



Aristidis M. Tsatsakis: Head of Departments of Toxicology and Forensic Medicine, Medical School, University of Crete, 71003 Heraklion, Crete, P.O. Box 1393, Greece. E-mail address: [email protected].

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Abstract

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Nano-particles (NPs) are used in industrial and biomedical fields such as cosmetics, food additives and biosensors. Beside their favorable properties, nanoparticles are responsible for toxic effects. Local adverse effects and/or systemic toxicity are described with nanoparticle

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delivery to target organs of the human body. Animal studies provide evidence for the

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aforementioned toxicity. Cardiac function is a specific target of nanoparticles. Thus, reviewing the current bibliography on cardiotoxicity of nanoparticles and specifically of

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titanium, zinc, silver, carbon, silica and iron oxide nano-materials is the aim of this study.

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Keywords: Nano-particle, Cardiac toxicity, Inflammatory marker, Reactive oxygen species.

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Abbreviations:

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NPs, nano-particles; ROS, reactive oxygen species; MDA, malondialdehyde; SOD; superoxide dismutase; GST, glutathione S-transferases; LDH, lactate dehydrogenase; CK, creatine

kinase;

AST,

aspartate

aminotransferase;

HBHD,

alpha-Hydroxybutyrate

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dehydrogenase; NMR, nuclear magnetic resonance; CK-MB, creatine kinase-MB; NO, nitric

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oxide; BNP, B-type natriuretic peptide; CRP, c-reactive protein; CPK-MB, creatine phosphokinase-MB; TNF- α, tumor necrosis factor alpha; IL-6, Interleukin 6; FGF2,

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fibroblast growth factor-2; I/R, Ischemia/Reperfusion; PCR, polymerase chain reaction;

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ELISA, enzyme-linked immunosorbent assay; VEGFA, vascular endothelial growth factor A; GSH, Glutathione; CAT, catalase; SWCNTs, single-walled carbon nanotubes; MWCNTs,

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multi-walled carbon nanotubes; BAL, bronchoalveolar lavage; IL-10, Interleukin 10; IL-12, Interleukin 12; MIP1-α, macrophage inflammatory protein 1α; Ccl11, Chemokine (C-C

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Motif) Ligand 11; ALT, alanine aminotransferase; ANG II, angiotensin II; ACE, angiotensin converting enzyme ; IV, intravenous; IT, intratracheal; MCP-1, monocyte chemotactic protein-1; hs-CRP, high-sensitivity c-reactive protein; IL-1β, interleukin-1 beta; p-VEGR2, phosphorylated/activated form of VEGF receptor 2; p-ERK1/2, phosphorylated/activated extracellular signal-regulated kinase (ERK)1/2, MEF2C, myocyte enhancer factor 2C; NKX2.5, homeobox protein Nkx-2.5; MRI, magnetic resonance imaging ; APX, ascorbate peroxidase.

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Introduction ............................................................................................................................. 4

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1.

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Contents

2. Cardiotoxicity and mechanism of nano-materials ...................................................................... 7 2.1. Titanium dioxide NPs........................................................................................................... 7

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2.2. Zinc oxide NPs ..................................................................................................................... 8

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2.3. Silver NPs........................................................................................................................... 10 2.4. Carbon NPs ........................................................................................................................ 11

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2.5. Silica NPs ........................................................................................................................... 13

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2.6. Iron oxides NPs .................................................................................................................. 13

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3. Conclusion ................................................................................................................................ 14 Conflicts of interest ....................................................................................................................... 14

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References ......................................................................................Error! Bookmark not defined.

1. Introduction Nanotechnology, a branch of bionanoscience, is a rapidly growing field which is of great importance to a series of industrial applications. As characterized by the United States Nanotechnology Initiative, nanoparticles (NPs) vary from 1 to 100 nm in dimension. Due to their novel thermal and electrical properties and their small size, engineered NPs seem lately to be the centre of focus in medicinal research as well to a variety of commercial purposes. In recent years, NPs have been used in different industrial fields such as aerospace, electronics, optical devices and computer products[1].

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At the same time, as demand for new medicines is growing, and given the inherent nanoscale size of the biological constituents of living cell, nanotechnology is evaluated in various medical fields like oncology and cardiovascular medicine. In fact, NPs are used to

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improve drug delivery as well as drug and biomarker research[2].

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Delivery of stem cells, inhibition of NOX2 via siRNA and improvement of the mechanical properties of heart valves are examples of novel applications of NPs in heart

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disease [3-5].

However, as a new field with extensive use and growing interest, NPs could exert side effects that are now emerging. Titanium, zinc, silver, silica, iron and carbon-based

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nanomaterials are NPs whith potential harmful health effects. Human NPs exposure can unintentionally occur through a series of occupational and non-occupational scenarios.

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Industrial procedures such as welding, combustion and electronics production are examples of passive exposure to the said substances[1]. Day by day NPs accumulate and persist in the environment and so is the potential risk

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of toxicity due to their exposure. Genetic damage, inflammation, inhibition of cell

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division and oxidative stress attribute to NPs toxicity. Especially oxidative stress is frequently reported to play a central role in NPs-induced toxicity. Physicochemical

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properties of NPs including surface charge, particle size and chemical composition are thought to be the main factors involved in NPs ability to cause the increased production of reactive oxygen species (ROS) and therefore to lead to tissue oxidative damages[6]. Oxides of transition metals are used in various industrial and medicinal fields as drug

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delivery, textile industries and sunscreen preparations. Due to their high surface-tovolume ratio, metal NPs can provoke the generation of free radicals via Fenton reaction. Increased ROS levels and augmented apoptosis were described after exposure to Zn, Ti and Fe NPs[6]. Increased oxidative stress is responsible for the induction of the MAPK signaling pathway and increases the transcription levels of key molecules, such as Nrf2 and NF-κB. These factors in turn could provoke the augmented mRNA expression of a series of proinflammatory mediators who are involved in the pathogenesis of a variety of inflammatory diseases[7]. On the other hand, ROS are thought to play a key role in modulation of the microenvironment of cardiomyocyte. NPs exposure could lead to cardiac toxicity through increased ROS production. As studies in ischemia-reperfusion injury showed increased ROS levels and altered redox homeostasis are responsible for myocardial damage [8].

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ACCEPTED MANUSCRIPT NPs inhalation is proven to lead to cardiorespiratory diseases in mammalian models. With a freshwater fish as a model, specifically the white sucker (Catostomus commersonii), it was found that when it was exposed to ZnO NPs, parasympathetic input

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increased and heart rate decreased[9].

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At the same time, cytotoxic and genotoxic effects were observed when SICH cell line was exposed to Ag NPs. Altered oxidative status and decreased oxidative defenses were

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observed as GSH, SOD and CAT levels decreased.

NPs use has a lot to offer especially in the field of cardiovascular medicine. However, the aim of this study is to delineate the adverse effects of NPs use and their related

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different NPs are presented in figure 1.

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cardiotoxicity. Adverse cardiovascular effects and mechanisms of cardiotoxicity of

Fig. 1: Adverse cardiovascular effects and mechanisms of cardiotoxicity of six highly used nanoparticles. Increase; Decrease; Reg: regulation; Inh: inhibition.

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2. Cardiotoxicity of nano-materials and the underlying mechanisms

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2.1. Titanium dioxide NPs

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In comparison with other metal-based NPs, titanium derived NPs are used in large quantities. TiO2 NPs, the most common form of titanium NPs, are water-insoluble and odorless materials. Biocompatibility, optical, electrical and whitening properties of TiO2 are

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some of its interesting features which make it a valuable substance for a number of applications. It can be found in abundance in products like white pigments, sunscreens, and

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food colorants [1, 10].

Despite its widespread use, nano-sized TiO2 toxicity has not yet been completely understood. Recent toxicological studies have indicated harmful effects of TiO2 NPs in

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different biological systems and organs[11]. For instance, accumulation of TiO2 NPs in the

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brain induces the release and metabolism of neurotransmitters such as norepinephrine and 5hydroxytryptamine[1]. Thus, understanding the risks and hazards including cardiotoxicity

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associated with TiO2 NPs exposure and evaluation of its dose-dependent effects are of great importance. In the zebrafish, as a model of chronic toxicity, it was shown that Titanium NPs can translocate between organs, are capable of passing through the blood–heart barrier and accumulate in the heart [12].

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The exact mechanisms via these particles act in mammalian species and cause their toxic effects are not understood yet. Despite the effective function of blood–heart barrier, particular NPs can accumulate in heart tissues and exert their toxic effects [12]. Chronic exposure to TiO2 NPs resulted in sparse cardiac muscle fibers, inflammatory responses in tissue level, cell necrosis and cardiac biochemical derangement. Increased ROS levels (including superoxide radicals and hydrogen peroxide), reduced malondialdehyde (MDA) content and augmented DNA peroxidation in the cardiac muscle was observed following exposure to TiO2. Additionally, TiO2 attenuated the antioxidant enzymes activity, especially of superoxide dismutase (SOD) and glutathione S-transferases (GST) [10]. Spectroscopic assays demonstrated that TiO2 NPs directly bind to lactate dehydrogenase (LDH) and result in alteration of the secondary structure of LDH. Thus, it is

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believed that the nano-anatase TiO2 is responsible for a new metal ion-active site in LDH and subsequently for a LDH activity enhancement [13]. Bu and colleagues showed that administration of nano-anatase TiO2 into the

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abdominal cavity could increase the activity of creatine kinase (CK), LDH, AST, and HBDH.

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Elevated levels of these enzymes are indicators of myocardial injury. Also, NMR-based metabonomic approach showed that AST, CK and LDH activities were elevated in the heart

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tissues of TiO2 NPs-treated rats. Mitochondrial swelling was another feature of toxicity observed in those animals [14]. Increased troponin T, myoglobin, CK-MB and nitric oxide were detected. Also, caspase-3 was elevated in the cardiac tissue of TiO2-intoxicated rats.

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TiO2 NPs induced apoptosis is thought to occur via mitochondria mediated pathways. This effect may be due to increased mitochondrial permeability transition followed by the release

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of apoptogenic factors such as cytochorome c and activation of caspase-9 and caspase-3. With the use of the Comet assay it was demonstrated also that the said NPs induced DNA damage, a fact that was evident by an increase in DNA tail length[15].

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However, in order to understand better the cardiovascular impact of TiO2 NPs, further studies

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on specific effects of TiO2 NPs on action potential of cardiac cells, ion channels function, coronary blood flow, electrocardiogram changes and biomarker levels referring to myocardial

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derangement such as BNP and CRP. A summary of reports on titanium dioxide NPs are

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presented in Table 1.

2.2. Zinc oxide NPs

Zinc (Zn) favorable characteristics are vastly used in the production of alloys, paints and brass[16]. Recently, quantum effect, large surface area and reactive surface sites of nanoscale metal powders have made Zn an exciting choice[17]. The special properties of zinc oxide made it the fifth most applicable engineering-based nanomaterial in consumer products as it is used in large quantities in sunscreens, food additives and pigments [18].Zn NPs are used in semiconductors, paints and coatings. Exposure to these particles occurs through oral (main route), inhalation, intravenous and dermal contact. Wide use of these elements leads to human exposure intentionally or unintentionally[19].

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After oral administration of ZnO NPs, tissue absorption and accumulation occurs through interactions between zinc and sulfur-containing sites of the proteins. Kinetic profile studies on ZnO NPs showed that the majority of them are excreted via feces and a small

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amount is excreted via urine[20]. In vivo and in vitro studies showed that the adverse effects

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of ZnO NPs also involve their dissolved fractions such as zinc ions. In vitro exposure to ZnO NPs can also reduce mitochondrial membrane potential, increase ROS production, and

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activate apoptotic signaling pathways [21]. In vivo studies showed that the liver, spleen, heart, pancreas and bone are target organs following oral exposure to NPs of 20 to 120-nm diameter [22]. Rats exposed to occupational levels of air-borne ZnO NPs developed

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inflammation in lung tissue and exhibited myocardial damage following long-term exposure [23]. Additionally, ZnO NPs cause cardiorespiratory toxicity in fish model as the Catostomus

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commersnii. Heart rate declined in ZnO NPs-treated fish, possibly as a result of damage to gill neuroepithelial cells and a consequent increase in parasympathetic input to the cardiac pacemaker[9]. DNA damage, inflammation and apoptosis in rat’s heart have been observed

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when ZnO NPs were administrated orally. Elevations of troponin T, CPK-MB and myoglobin

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levels which are indicative of cardiac damage were also reported [24]. Remarkable increase in serum pro-inflammatory biomarkers including TNF-α, IL-6

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and CRP in rats intoxicated with ZnO NPs, were reported. The induction of such biomarkers may play a principle role in cardiac toxicity induced by ZnO NPs. It has been demonstrated that, in cultured cardiac myocytes, TNF-α increased the production of reactive oxygen species (ROS) resulting in DNA damage [25]. Also, up-regulation of TNF-α can lead to

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increase in other cytokines such as IL-6 which is known as the chief stimulator of CRP production[26].

These particles may cause cardiac toxicity via disturbing calcium homeostasis. ZnO NPs can affect calcium permeability and may result in accumulation of Ca2+ in cytosol. This phenomenon is associated with the pathogenesis of myocardial injury[27]. Baky and colleagues showed that ZnO NPs induced cardiac DNA fragmentation evident by a significant increase in the DNA tail length and of % DNA bases in the tail in cardiac samples of rats intoxicated with ZnO NPs. DNA damaging potential of ZnO NPs was confirmed by several experimental studies[28, 29]. Damages to DNA backbone and bases were reported following ROS generation[30]. One of the most important events after DNA damage is apoptosis [25]. Elevated levels of caspase-3 were observed in rats exposed to ZnO NPs, proposing that apoptosis is related to DNA damages [24]. Unfortunately, there were just a couple of studies that showed

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adverse effects of ZnO NPs on cardiac tissue. Thus, complementary research is necessary to provide a better understanding of the toxic aspects of these substances. Table 2 depicts studies on zinc oxide NPs.

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2.3. Silver NPs

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Silver (Ag), is a soft, white bright metal. Silver coins and jewelry are used in large quantities. Industrially, silver is used in mirrors, photography and conductor tools[1]. Silver NPs have been developed as potent antimicrobial agents and have a variety of applications in toothpastes, bedding, water purification and nursing bottles [31, 32]. After oral exposure, it is

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shown that about 18% of silver could be absorbed in humans. Animal studies showed that it is distributed to all body organs and the majority of it is excreted in bile [33].

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Recently, numerous studies have reported silver nano-materials adverse effects including cytotoxicity and ROS generation [34, 35]. Noticeable decrease in function and membrane integrity of mitochondria, increased levels of inflammatory cytokines and several

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other toxic effects were observed in alveolar macrophages [31]. In PC12 cell line, silver NPs

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induced irregular membrane borders and cell shrinkage [36]. Silver NPs exposure enhanced superoxide anion production and caused deleterious effect in heart tissue and led to oxidative

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stress and inflammation in rats [37]. Heart rate retardation in medaka embryos (Oryzias latipes) was reported by Cho et al.[37]. After sub-chronic (dermal) application of Ag NPs in guinea pigs, it was found that the said nanoparticles accumulate in different organs such as

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the heart and cardiomyocytes deformity is observed[38]. Fibroblast growth factor-2 (FGF2) in the heart contributes to pathological states such as hypertrophy, atherosclerosis and ischemia/reperfusion (I/R) injury [39, 40]. By means of PCR and ELISA methods, it was shown that FGF2 mRNA expression level was downregulated in chickens that received 20 ppm of Ag NPs. On the other hand, vascular endothelial growth factor A (VEGFA) which is an angiogenesis modulator in the heart was up-regulated at the same dose [40-42]. Measurement of GSH content, SOD and catalase confirmed the noxious effect of silver NPs due to oxidative stress in A431 and HT-1080 cell lines. Another study showed that Ag NPs significantly diminished GSH content, decreased SOD and catalase activities and increased lipid peroxidation in SICH cell line in a concentration-dependent manner. Also, condensation and fragmentation of nuclei was shown by comet assay [31]. A summary of studies on silver NPs is given in Table 3.

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2.4. Carbon NPs

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Carbon (C) can be found in a wide range of substances. Depending on binding sites,

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this atom can form different allotropes such as graphite and diamond. As an allotrope of carbon, single-walled carbon nanotubes (SWCNTs) are composed of a sheet of graphene with

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a diameter of 1–4 nm and a length ranging from 100 nm to 1.5 mm. Because of versatile chemistry, SWCNTs exhibit a wide range of application in cancer therapy, drug delivery, gene therapy, sensors, conductive plastics, paints and technical textiles [43, 44].

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Small particle size, large surface area and ornamentation with catalytic metals are the factors which make SWCNTs toxic agents. These conditions result in ROS generation and

deleterious effect on cells [44-46].

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oxidative damages by Fenton reaction, a recognized pathway via which SWCNTs yield their

Graphite sheets with a nano-scale diameter can produce another form of carbon nanotubes

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called multi-walled carbon nanotubes (MWCNTs) [47]. Because of special physical

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compositions and inherent designs, these particles have been used in biomedical, electronic, computer, and aerospace products[48].

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Inhalation is the main route of exposure to carbon NPs. Thus, lung is the first organ exposed to toxic effect of these particles. Consequently, these NPs are transported to secondary organs [49, 50]. After the pulmonary contact with carbon NPs, liver and kidney necrosis, inflammation, microvascular abnormality, depletion of serum antioxidant and other

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toxic effect may occur [43]. Mercer and colleagues showed that MWCNTs settled in the lungs were also distributed to the heart, brain, liver and kidney [51]. After exposure to SWCNTs, levels of carbon-centered lipid-derived radicals were elevated in the lung, heart and liver. Pulmonary exposure to SWCNTs leads to oxidative damage and recruitment of inflammatory factors in the bronchoalveolar lavage (BAL) fluids. Systematic toxicity may occur after a week of exposure which is characterized by a decrease in thiol contents, an elevation in lipid-peroxidation products and an increase in inflammatory indices in the heart and liver [43]. I/R play an important role in the pathophysiology of myocardial damage [52]. Also, a direct correlation between inflammatory cytokines (i.e. IL-6, IL-10, and IL-12) and I/R injury has been reported. MIP1-α is another factor which is implicated in I/R injury in myocardial tissue [52].

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The effects of MWCNTs on myocardial ischemia-reperfusion (I/R) injury model were investigated by Urankar et al. [52]. Post I/R myocardial infarction worsened in a dose and time-dependent manner following intratracheal (IT) instillation of multi-walled carbon

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nanotubes. MWCNTs caused elevated levels of inflammatory mediators. Eotaxin levels were

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increased after exposure to MWCNTs and a correlation between serum eotaxin (eosinophil chemotactic proteins) levels and cardiac injury, heart failure and regulation of

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inflammatory cell was observed. Eotaxin is mainly secreted by smooth muscle cells and fibroblasts and its production in generally related to involvement of eosinophils and basophils in certain inflammatory conditions [53-55].

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Pulmonary exposure to carbon NPs can lead to liver and myocardial damage and result in mild alteration in ALT, AST, LDH and CK levels in serum. SWCNT phagocytosis

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in lung epithelium may induce production of pro-inflammatory factors, which play a key role in local and systemic inflammatory responses. When SWCNTs were instilled into the lung of hypertensive rats, alterations in cardiovascular and pulmonary system occurred 24 and 72 h

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post instillation. Significant increases of ET-1 and ACE levels in plasma were observed in

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treated animals [44]. In another animal study, it was found that MWCNT inhalation could lead to impairments of endothelium-dependent dilation in the coronary microcirculation

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within 24 h, a condition from which full recovery was not achieved within 168 h [56]. Animal studies on embyogenesis showed that chicken embryos heart vascularization was significantly reduced following exposure to diamond and graphite NPs. At the same time, mRNA and protein expression of the proangiogenic basic fibroblast growth factor (b

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FGF) was decreased in heart tissue[57]. Similarly using the chick chorioallantoic membrane (CAM) model, carbon-based nanomaterials as carbon nanotubes and fullerene as well as graphite proved to be anti-angiogenic in the presence of 2 pro-angiogenic factors, the vascular endothelial growth factor (VEGF) and the basic fibroblast growth factor (FGF2), with a relatively greater potency in inhibiting VEGF versus FGF2 by the said carbon materials [58]. Intravenous (IV) and intra-tracheal (IT) administration of C60 caused myocardial infarction in rats. Coronary artery contraction was indicated, after IT exposure to C60. Thompson et al. demonstrated that IV and IT administration of C60 fullerene resulted in expansion of myocardial infarction in Sprague-Dawley rats following I/R injury. In animals that received C60 IV, elevated concentration of IL-6 and MCP-1 were observed [59]. It was observed that IT instillation of MWCNT caused arrhythmogenic effect, increased ET-1 release and depressed coronary flow in Sprague-Dawley rat. These events

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may contribute to post-I/R myocardial infarct expansion [60]. Some of studies on carbon NPs are mentioned in Table 4.

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2.5. Silica NPs

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Silica is an oxide form of silicon [61]. Silica NPs are ranked among top five of mostly used nano-materials in commercial products and are used in drug delivery, gene therapy, diagnosis, papermaking and cosmetics [62]. In addition, due to its higher biocompatibility than other imaging NPs, silica NPs were introduced as ideal tools for medical

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photography[1].

Because of low density, these substances can readily mix with air. Inhalation is the main

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route of exposure in the work places during production and storage [63, 64]. Lung is the first organ which is adversely affected and this may lead to systematic toxicity (e.g. cardiovascular inflammation) [65].

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Recently, silica NPs were used for delivery of adenosine, a prototype cardioprotective agent,

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into I/R heart tissue [66]. Silica NPs are capable of producing ROS which may lead to cytokine release and apoptosis [67].

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In rats IT administration of silica NPs cause hs-CRP level elevation in a sizedependent manner and TNF-a, IL-6, and IL-1β levels increase. These particles cause inflammation in cardiovascular system. ET-1, D-dimer, LDH and CK-MB increased after

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silica NPs exposure [64].

MEF2C is a key factor in cardiac morphogenesis and myogenesis before the formation heart tube [68, 69]. NKX2.5 is another agent which regulates heart development in humans. Genetic insufficiency in NKX2.5 contributes to atrioventricular defects [70]. Histamine can be used as a marker of myocardial ischemia and its release usually results in coronary vasoconstriction. Elevated levels of histamine were observed by Chen et al. Increased levels of cTnT which is indicative of acute myocardial injury were observed in old rats which were exposed to aerosol of silica NPs [63]. Table 5 gives a summary of reports on silica NPs.

2.6. Iron oxides NPs Superparamagnetic and physicochemical properties of iron oxide NPs are important features for medical and industrial applications. Iron oxide NPs act as a contrast agent in

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positron electron tomography, magnetic resonance imaging and ultrasound. In addition, they are used in drug and gene delivery, cancer therapy and catalysis[1]. After subcutaneous injection, superparamagnetic iron oxide NPs were distributed in heart,

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lung, kidney, liver and spleen [71]. Due to generation of ROS, iron oxides NPs result in

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oxidative damage. Subsequently, cytoskeletal disruption, decrease in proliferation and cell death occurred [72]. On the contrary, using confocal microscopy, it was also reported that

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negatively charged superparamagnetic iron oxide NPs did not affect the actin cytoskeleton of heart cells significantly while they markedly disrupted the actin cytoskeleton in kidney and brain cells (similar results were reported from in vivo experiments). Increased vascular

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permeability was reported after exposure to these particles [73]. In another study slight change of cell viability and genetic content was observed [74, 75]. Acute heart rate reduction

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was observed when BALB/c mice received 10 mg/kg polyacrylic acid coated γ-Fe2O3 NPs [75]. Effect of Fe2O3 and Fe3O4 NPs (0.001– 100 μg/ml) on endothelial cells of heart microvascular were assessed by Sun et al. Result of their study revealed that these particles

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did not change plasma membrane permeability and inflammatory factors, significantly [73].

3. Conclusion

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A summary of investigations performed on iron oxide NPs is given in Table 6.

Because of the unique properties of nano-materials, these substances are widely used

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in biomedical and industrials fields. Understanding all aspects of nano-material safety is of great importance. In recent years various studies showed specific organ toxicity of these substances especially of the heart, brain and lung. Although discrepancies are observed among published studies, nano-scale materials seem to affect heart tissue and vigilance is needed in their broad and augmented application. Further research and heart functional studies especially with the use of echocardiography are needed for the better understanding of the possible heart toxicity of nanoparticles.

Conflicts of interest We declare no conflict of interest.

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Table 1. Cardiotoxic properties of TiO2 NPs. Experimental

Treatment

model

protocol

Main results

Proposed

Referen

mechanisms

ce [76]

Male

and

A single dose

No apparent damage was seen in the

Probably due to late

Female

ICR

of TiO2 NPs (0,

heart

onset

and

1387

mg/kg

BW)

was

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damages.

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140, 300, 645,

injected

and evaluation

14 days later. Animals

were

Increased

rats

treated

with

myoglobin, TNF-ɑ, Il-6, NO, IgG,

TiO2 (600 and

VEGF, serum glucose and calcium, C-

directly

1000 mg/ kg

reactive

and

phosphate

/day, orally) for

increased

and

and/or

5

augmented DNA damage.

protein,

activity

Nanoanatase

TiO2

NPs

lead

(via

DNA

indirectly stress)

damage DNA. Higher

TiO2 (5, 10, 50,

Even at high doses, heart weight /body

toxicity

100,

and

weight values were not significantly

inflammation.

150mg/kg/day)

different from controls. Titanium heart

were

injected

tissue levels were lower than those of

the

other evaluated organs (namely, liver,

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[77]

moiety)

An LD50 of 150 mg/kg was found.

in

to

genotoxicity as they

(oxidative

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caspase-3

CK-MB

T,

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mice

troponin

TE

days ICR

of

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Wistar albino

Female

levels

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was performed

consecutive

myocardial

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mice

of

abdominal

kidney, spleen, lung and brain).

cavity for 14

Although AST, CK, LDH, and alpha-

days.

HBDH activities at 5 and 10 mg/kg

doses

cause

[78]

and

was not different from the control, at 50,

100,

and

parameters

150 were

mg/kg

these

significantly

increased implying that myocardium damage occurs at higher doses.

ICR mice

female

Intragastric

Heart parameters and titanium heart

TiO2

administration

tissue levels were significantly and

oxidative

of

nano-TiO2

dose-dependently increased. Evidence

excessive

(2.5, 5, and 10

of myocardial pathology increased in a

production and lipid

mg/kg/day) for

dose-dependent manner (e.g. severe

peroxidation and

90 days.

inflammatory

weakening

cell

infiltration

on

NPs

induce

stress

by ROS

the

by anti-

[79]

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tunica externa at 5mg/kg and cell

oxidant defense.

necrosis at 10 mg/kg). The levels of O2–,

H2O2,

(MDA),

and

lipid

peroxidation

protein peroxidation

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(protein carbonyl), as well as DNA

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damage were increased. The activities of SOD, catalase (CAT), ascorbic acid (APx),

glutathione-S-

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peroxidase

transferase (GST), and glutathione

reductase (GR) were decreased with

increasing doses of TiO2. Increased

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levels of creatine kinase reflected myocardial damage. Fish

were

Titanium heart tissue levels were

Despite the presence of

zebrafish

exposed to 1.0,

comparable with brain levels and both

blood–brain barrier and

(Danio rerio)

2.0, 4.0, 5.0,

were dose and time-dependant.

blood–heart

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wild-type

7.0 mg/l TiO2 and

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months

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NPs for up to 6

randomly

[80]

barrier,

nanomaterials are able to pass (due to their very small size) and induce toxic effects.

sampled every

Rat

Lactate

In

CE P

2 months.

vitro

While at lower TiO2 concentrations

TiO2

to

LDH activity was increased, it was

secondary

decreased at higher concentrations.

and

exposure

e

TiO2 (5 nm)

Rats

AC

dehydrogenas

A single

Decreased action potential period,

intratracheal

impairment of sarcomere

dose of TiO2

shortening and diminished stability

NPs (2

of resting membrane potential

mg/kg).

were observed, in vitro. Increment

Also, isolated

of cardiac conduction velocity and

cardiomyocyt

tissue excitability (increased

es were also

chance of arrhythmias).

exposed to TiO2 NPs, in vitro

changes

LDH

[81]

structure

increases

its

activity.

ROS overproduction

[82]

ACCEPTED MANUSCRIPT

17

Table 2. Cardiotoxic properties of ZnO NPs. Treatment

model

protocol

Main results

and

Nanoscale zinc

Only fatty degeneration was seen in

female

CD-

5

Zn/kg

the cardiovascular cells. An apparent

(samples taken

rise was seen in lactate dehydrogenase

14 days after

(LDH), aspartate aminotransferase

the

(AST), creatine kinase (CK) and

gastrointestinal

hydroxybutyrate

administration)

(HBD) levels (conventional cardiac

mechanisms

ce [83]

SC R

ICR mice

g

Referen

IP

Male

Proposed

T

Experimental

dehydrogenase

NU

enzymes). Male Sprague-

Intratracheal

After 3, 6 and 12 hr, Zn heart tissue

Systemic inflammation

Dawley rats

administration

levels were not significantly different

and

of 10 mg/ml

from controls but 24 hr post-exposure

disturbance.

ZnO NPs

they reduced significantly.

MA

oxidative

Exposure

to

Rat’s heart samples showed focal

Dawley rats

ZnO NPs for 2

fibrosis, myocardial degeneration and

weeks (5 h/day

necrosis 7 days post exposure.

TE

D

Male Sprague-

and

5

CE P

days/week) white suckers

[84]

Fish

exposed

were

Fish treated with ZnO showed a

Gill

to

significant 35% reduction in heart rate

cells injury possibly

following 15 and 20 h treatment

resulted

ZnO NPs (1.0

in

parasympathetic input to

the

cardiac

pacemaker

Wistar albino

Oral

Serum

rats

administration

(TNF-α, Il-6 and CRP), troponin-T,

of

and

CK-MB, myoglobin, serum VEGF

1000 mg/kg for

(angiogenic factor), NO (oxidative

5 days

stress marker), and cardiac calcium

600

[85]

enhancement of

AC

mg/L) for 25 hr

neuroepithelial

pro-inflammatory

markers

level, caspase-3 activity and DNA damage were increased at both doses of ZnO NPs as compared to control animals.

[86]

ACCEPTED MANUSCRIPT

18

Table 3. Cardiotoxic properties of Silver NPs. Experimental

Treatment

model

protocol

mechanisms

ce [87]

Oral

A non-significant increase in CPK-

Heart injury was not

administration

MB as compared to control animals.

accompanied

of silver NPs (3

Histopathological

increase in CPK-MB

mg/kg/day, 10–

showed mild edema and separation of

25 nm particle

myofibrils.

size)

for

examination

21

days

Superoxide anion production was

Inflammatory

Dawley rats

administration

increased by 41% in heart tissue.

responses

NU

Oral

500

mg

and

India

24-hr exposure

At concentrations >2 μg/mL, NPs

Ag

Catla

catla

to 2, 4, 8, 16,

were toxic for SICH. A concentration-

oxidative

heart cell line

32

64

dependent increase of tail DNA (%)

cytotoxicity

(SICH)

μg/mL of Ag

was detected. While not significant at

genotoxicity.

NPs

2 and 4 μg/mL, a significant decrease

TE

D

Sahul

and

[88]

oxidative stress.

MA

silver NPs/kg

an

levels.

Male Sprague

of

by

T

rats

Referen

IP

Wistar

Proposed

SC R

Male

Main results

NPs

induce

[89]

stress, and

in CAT, SOD and GSH was observed at 16, 32 and 64 μg/mL.

Intratracheal

Although IT administration of Ag NPs

Probably

Dawley rats

(IT) instillation

did

of

sensitize the immune

of

citrate

proinflammatory markers (IL -1b, IL-

system resulting in a

AgNP

2, IL-5, IL-6, IL-10, IL-13, IL-17a,

more marked response

(200 µg). After

IL-18, MCP-1, IFN-γ, RANTES, and

in

24 and 168 hr,

TNF-α), heart rate and QT interval,

myocardial

myocardial

the levels of IL-2, IL-6, and IL-18

reperfusion injury.

CE P

male Sprague

AC

capped

ischemia

(by

not

significantly

affect

the

increased

level

after

the

Ag

setting

NPs

[90]

of

ischemia

I/R.

ligation of left

Treatment with Ag NPs worsened the

anterior

outcomes of I/R without inducing

descending

systemic inflammatory reactions or

coronary artery

electrical disturbances.

for 20 min) and subsequently reperfusion (for 2hr)

were

induced. Male Sprague-

Five-hour

Dawley rats

exposure

by

cardiovascular parameters remained

Short-term exposure to

unchanged on day 1 and 7 d post

Ag NPs does not cause

[91]

ACCEPTED MANUSCRIPT

19

inhalation

to

exposure.

acute

100 (equal to

cardiovascular

toxicity.

20 mg/L total silver)

μg/m3

T

1000

and

total

silver)

SC R

mg/L

IP

(equal to 200

Broiler

Birds

were

At 20 ppm, Ag NPs augmented the

chickens

treated

with

expression of VEGFA gene, and

water

reduced FGF2 gene expression at

solution containing

mRNA and protein level.

NU

oral

10

or 20 ppm of

MA

Ag NPs Oryzias

Embryos were

Following a 7-day exposure to Ag

latipes

exposed

NPs (0.8 mg/l), a significant decrease

(medaka)

0.1−1 mg/l of

embryos

Ag NPs for 14 days Brain, heart

male Wistar

and skeletal

rats

muscle

D Creatine kinase was inhibited in brain

Silver NPs potentially

and

interact with

CE P

Adult and

[93]

in heart beat was recorded.

TE

to

[92]

skeletal

muscle;

however

it

remained unaffected in the heart.

homogenates

[94]

sulphydryl moieties of CK.

were treated

AC

with silver NPs (10, 25 and 50 mg/l) for 1 hr

Albino zebrafish

Si NPs (1 to 12

Pericardial edema and bradycardia while no

SiNPs inhibited calcium

mg/mL) via

effect on atrioventricular conduction. Cardiac

signaling pathway and

intravenous

output dose-dependently decreased.

decreased cardiac

microinjection for

Oxidative stress and neutrophil-mediated

contraction via down-

24 hr.

cardiac inflammation were observed.

regulation of related genes, such as ATPase-related genes (atp2a1l, atp1b2b, atp1a3b), calcium channelrelated genes (cacna1ab,cacna1da) and the regulatory gene tnnc1a for cardiac troponin C.

[95]

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20

Table 4. Cardiotoxic properties of carbon NPs. Experimental

Treatment

model

protocol

Male

Rats

spontaneously

Main results

Referen

mechanisms

ce

Probably

intratracheally

in the left ventricle and myofiber

inflammatory

hypertensive

exposed to Fe-

degeneration. Fe-rich NPs post 72-h of

responses

rats

poor SWCNTs

exposure caused more marked heart

oxidative stress.

and

tissue derangement.

SWCNTs. Adult female

A

single

C57BL/6mice

pharyngeal

to

7 days post-exposure, only at 80 μg

Increased

treated animals, LDH levels and

inflammation

and and

[97]

of

myeloperoxidase activity in heart

oxidative

stress

SWCNTs

(40

tissue homogenates increased by 22%

depleted

antioxidant

80

and 15-34%, respectively. SWCNTs

defense.

exposure at 40 and 80 μg/mouse caused

MA

μg/mouse)

NU

aspiration

and

[96]

and

IP

Fe-rich

due

T

SWCNTs caused histological damages

SC R

were

Proposed

heart

tissue

thiols

levels

reduction by 7 and 10%, respectively

D

and elevated carbonyls levels by 24

TE

and 44%, respectively. Male

A single dose

Administration of MWCNT dose and

C57BL/6J

of

time-dependently

mice

(0.01, 0.1, 1, 10

myocardial infarction and the severity

and 100 μg) in

changes with different forms of the

3

particles.

CE P

MWCNT

forms

AC

(unmodified, commercial grade,

and

functionalized)

worsened

[98]

ACCEPTED MANUSCRIPT

21

Table 5. Cardiotoxic properties of silica NPs. Proposed

Referen

protocol

mechanisms

ce

male Sprague-

Animals

myocardial

Ischemia may be due

[99]

Dawley

inhaled

ischemia was reported (more marked

to an increase in whole

nanoparticles

with

blood viscosity which

weeks (65 g),

for 40 min per

Troponin-T (as a marker of acute

8 weeks (265

day

myocardial

g),

weeks.

rats

of

3

and

months

20

An SiO2

for

4

age-dependent

increasing

significantly

(670

age).

Cardiac

ischemia)

T

model

Main results

IP

Treatment

may in turn increase

was

peripheral

vascular

Cardiac

resistance,

decrease

SC R

Experimental

increased.

rhythm was altered only in older rats.

MA

NU

g) old.

perfusion

of

the

coronary

artery

and

facilitate

thrombosis

resulting in increased risk

of

myocardial infarction.

Myocytes were

After 10 min of incubation, MCM41-

MCM41-cal

myocytes

exposed to 200

cal and SBA15-cal either attached to

SBA15-cal

isolated from

μg/mL

the plasma membrane or entered

reasonable

male

MCM41-cal or

ventricular myocytes.

bioavailability

Male

SBA15-cal

Wistar

(two types of

min following intravenous injection

calcined

(2.0 mg/mL), MCM41-cal passed in

rats for in vivo

Mesoporous

the

experiments

silica

ventricular myocytes and localized

microparticles)

around the mitochondrial membranes.

AC

[100]

show

In vivo results showed that within 10-

CE P

rats

and

TE

Wistar

D

Ventricular

of

acute

perivascular

space,

entered

for 10 min

Human

Cells

were

According to TEM images, NPs

Cell death was induced

umbilical vein

treated

with

entered the cells (mostly found in

by oxidative stress and

endothelial

silica

perinuclear region). Cell viability

apoptosis.

cells

nanoparticles

decreased and LDH activity (as a

(HUVECs)

(25, 50, 75 and

marker

100 μg/mL) for

increased with increasing dose and

24 hr.

time. NPs induced early and late

of

membrane

damage)

apoptosis and the latter was much more marked. NPs increased ROS production and reduced SOD activity in a dose-dependent manner.

[101]

ACCEPTED MANUSCRIPT

22 of

silica

In vivo study, showed that treatment

the AB strain

nanoparticles

with

(wild-type) for

(25,50, 100 and

malformations such as pericardial

in

200 μg/mL) for

edema.

vivo

experiments

4-96

hr

NPs

caused

embryonic

post

T

Zebrafish

For all diameters, NPs heart tissue

with diameters

concentration

of 30, 60, 90,

increasing

and

concentrations were seen for 30 nm

600

nm

Higher

and lower concentrations for 600 nm

administered

NPs. While GSH content remained

(intratracheally

unchanged, SOD decreased and ROS

16 times every

and MDA levels increased with the

other day) at

increase of dose and diameter. LDH

three doses of

and

2, 5 and 10

significantly in all treated groups.

CK-MB

particles

(50–

200 nm with

dominant

diameter) was injected.

[102]

oxidative stress, and ROS generation

D

increased

Particles

groups were not different from the

accumulate

control group.

tissue.

CE P

150 nm as the

levels

NPs heart tissue levels of experimental

TE

0.5 mg of SiO2

AC

rats

Wistar

doses.

with

were

mg/Kg male

increased

Inflammatory reaction,

SC R

rats

Silica particles

NU

Wistar

MA

Male

IP

fertilization

do

not

in

heart

[103]

ACCEPTED MANUSCRIPT

23

Table 6. Cardiotoxic properties of iron oxide NPs. Proposed

Referen

model

protocol

mechanisms

ce

human cardiac

Fe2O3

Following 12 and 24 h treatments, no

Probably due to their

[104]

microvascular

Fe3O4 NPs

marked decrease in cell viability was

large specific surface

endothelial

0.001-100

seen. A non-significant increase in

area

cells

μg/ml)

LDH leakage (as a marker of cell

and (

(HCMECs)

membrane

integrity)

and

ROS

T

Main results

IP

Treatment

SC R

Experimental

production was recorded. Also, this

treatment did not affect endothelial permeability

nor

the

mRNA

NU

expression of inflammatory markers

(Vascular cell adhesion molecule-1,

MA

intercellular adhesion molecule 1, macrophage cationic peptide-1 and IL-8).

mice

Either a single

In macrophages of multiple organs, no

The

dose

of

iron-positive pigment was reported

accumulation

100mg/kg or a

from histopathological studies and the

marked.

10-day repeated

of

level

of is

[105]

not

level of NPs between single and multiple dose treatment was not significantly different.

CE P

administration

D

KM

TE

Male

Superparamagn

AC

etic iron oxide (SPIO)

(subcutaneousl y)

Sprague-

Fe2O3@DMSA

Infarction size in NPs-treated groups

NPs protected

Dawley rats

(0.1, 0.25, 0.5

was significantly lower compared to

myocardium from

mg Fe /kg/day)

saline-treated animals. SOD activity in

ischemia and this

for 7 days.

NPs-treated animals (0.5 and 0.25

effect depends on core

mg/kg) was significantly higher but

sizes but not on

MDA,

molecules used to coat

LDH,

activities and

CK,

and

CK-MB

MDA content were

[106]

NPs.

significantly lower. Mice

Intravenous

NPs enhanced plasma plasminogen

Oxidative stress

administration

activator inhibitor-1 (PAI-1) levels.

evident by augmented

of ultrasmall

Moreover, they increased creatine

lipid peroxidation

superparamagn

phosphokinase-MB isoenzyme (CK-

markers, reactive

[107]

ACCEPTED MANUSCRIPT

24

etic iron oxide

MB), lactate dehydrogenase (LDH)

oxygen species and

nanoparticles

and troponin-I levels in plasma.

superoxide dismutase

(0.4, 2 and 10

activity in the heart.

μg/kg) Mitochondrial respiratory chain

Fe3O4 exposure had no

mitochondria

complexes activities remained

toxic effects on

from brain,

unchanged in all tissues and at all

heart, liver,

concentrations of iron oxide

lung and

nanoparticles.

IP

T

Isolated

mitochondrial coupling

SC R

and respiratory chain complexes I, II, III,

kidneys were

and IV activities,

exposed to

probably due to

NU

Fe3O4 (0, 100, 200, 300 and 500 µg/ml) for

CE P

TE

D

MA

30 min at 25oC.

AC

Wistar rats

insufficient duration of exposure.

[108]

ACCEPTED MANUSCRIPT

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Graphical abstract