Arsenic cardiotoxicity: An overview

Environmental Toxicology and Pharmacology 40 (2015) 1005–1014

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Environmental Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/etap

Review

Arsenic cardiotoxicity: An overview Nafiseh Sadat Alamolhodaei a , Kobra Shirani b , Gholamreza Karimi c,∗ a

School of Pharmacy, Mashhad University of Medical Sciences, Iran Department of Pharmacodynamy and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran c Pharmaceutical Research Center and Pharmacy School, Mashhad University of Medical Sciences, Iran b

a r t i c l e

i n f o

Article history: Received 30 April 2015 Received in revised form 25 August 2015 Accepted 30 August 2015 Available online 3 September 2015 Keywords: Arsenic Cardiotoxicity QT prolongation Medicinal plants

a b s t r a c t Arsenic, a naturally ubiquitous element, is found in foods and environment. Cardiac dysfunction is one of the major causes of morbidity and mortality in the world. Arsenic exposure is associated with various cardiopathologic effects including ischemia, arrhythmia and heart failure. Possible mechanisms of arsenic cardiotoxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels. Several evidences have shown that mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic induced apoptosis. Arsenic trioxide is an effective and potent antitumor agent used in patients with acute promyelocytic leukemia and produces dramatic remissions. As2 O3 administration has major limitations such as T wave changes, QT prolongation and sudden death in humans. In this review, we discuss the underlying pathobiology of arsenic cardiotoxicity and provide information about cardiac health effects associated with some medicinal plants in arsenic toxicity. © 2015 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 Arsenic exposure and cardiac adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 Mechanisms of As-induced cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 3.1. Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006 3.2. Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 3.2.1. ROS-mitochondrial disruption and caspase activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 3.2.2. MAPK signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008 3.3. Changes in cardiac ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008 3.3.1. Potassium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008 3.3.2. L-type calcium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008 3.4. Changes in endothelial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009 Clinical presentations and arsenic detoxification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 4.1. Acute poisoning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1010 4.2. Chronic poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 Role of medicinal plants against As cardiac adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 5.1. Boerhavia diffusa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 5.2. Corchorus olitorius . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010 5.3. Salvia miltiorrhiza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012

Abbreviations: AS, arsenic; As2 O3 , ATO arsenic trioxide; AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; BDE, Boerhavia diffusa; BFD, blackfoot disease; CAT, catalase; CK-MB, creatine kinase-MB fraction; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated protein kinases; GSH, glutathione; GPX, glutathione peroxidase; GR, glutathione reductase; GMCSF, granulocyte-macrophage colony-stimulating factor; IHD, ischemic heart disease; JNK, c-Jun N-terminal kinases; LQTS, long QT syndrome; LDL, lactate dehydrogenase; NR, neutral red; ROS, reactive oxygen species; SB, silibinin; SOD, superoxide dismutase; SalB, salvanoic acid B; TA, terminalia arjuna; TGF␣, transforming growth factor-␣; VED, vascular endothelial dysfunction. ∗ Corresponding author. E-mail addresses: [email protected] (N.S. Alamolhodaei), [email protected] (K. Shirani), [email protected] (G. Karimi). http://dx.doi.org/10.1016/j.etap.2015.08.030 1382-6689/© 2015 Elsevier B.V. All rights reserved.

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5.4. Silibum marianum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 5.5. Terminalia arjuna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012

1. Introduction Arsenic is a ubiquitous metalloid element in rock, soil, water and air. It is abundant in the earth’s crust and biosphere (Sumi et al., 2011). This element exists in two forms: organic and inorganic. Both of them are present in the environment and human body (Tseng, 2008; Jomova and Valko, 2011). When arsenic is combined with hydrogen and carbon, it is called organic arsenic. Inorganic form is referred to combination with some elements such as sulfur and oxygen. Numerous studies have indicated that inorganic arsenic in contaminated drinking water is more toxic than organic form (Balakumar and Kaur, 2009; Das et al., 2010) and it can be found in crustacean seafood (Hirano et al., 2003; Manna et al., 2008). Inorganic arsenic is in two valence states: trivalent (arsenite) and pentavalent form (arsenate). In general, arsenite is more toxic than the arsenate (Landrigan, 1982; Manna et al., 2008). Recent studies have shown that arsenic toxicity in drinking water is a serious problem in Asian countries such as Bengal (India) and Bangladesh. Also, some other countries like Taiwan and Chile have arseniasis hyperendemic areas (Landrigan, 1982; Mathews et al., 2013). The last standard concentration of inorganic arsenic (0.01 mg/ml) in well-water was established by World Health Organization in 1993 (Balakumar and Kaur, 2009). Human exposures to arsenic occur through environmental, occupational and medicinal sources (Mumford et al., 2007; Alissa and Ferns, 2011; Mathews et al., 2013). The major environmental source of arsenic is contaminated well-water with high arsenic concentration. Medicinal sources refer to Fowler’s solution for psoriasis and arsenic trioxide used to treat acute promyelocytic leukemia (Mathews et al., 2013). Chemical workers and pesticide applicators are at the highest risk for occupational exposure (Landrigan, 1982). The possible human exposure routes and the natural and industrial sources of arsenic have been depicted in Figs. 1 and 2. Current evidences are sufficient to infer the relationship between arsenic exposure and cardiovascular diseases (Alissa and Ferns, 2011). The purpose of this paper is to provide some informations about arsenic cardiotoxicity and to present some cardioprotective medicinal plants. 2. Arsenic exposure and cardiac adverse effects Heart disorders such as arrhythmias and ischemic heart disease are the number one cause of human death in several countries (Manna et al., 2008; Das et al., 2010). Both environmental and occupational exposures to inorganic arsenic are associated with myocardial injuries (Alissa and Ferns, 2011). In fact, arsenic plays a crucial role in the abnormalities of cardiac tissue. Although the whole organs in the human body are affected by arsenic toxicity, heart as a vital organ is the most important (Manna et al., 2008). Majority of studies support the notion that chronic arsenic exposure in drinking water is associated with various cardiovascular disorders (Tseng, 2008; Balakumar and Kaur, 2009; Jomova and Valko, 2011). A systematic review in Taiwan showed the association between arsenic in drinking water and

cardiovascular diseases (Tseng, 2008). A clear relationship was found between uterus myocardial infarction and arsenic exposure in well-water in Chile (Yuan et al., 2007). In the United States, prenatal cardiovascular anomalies were reported in a populations exposed to arsenic from drinking water (Hopenhayn-Rich et al., 2000). Based on a cohort study in Bangladesh, arseniccontaminated drinking water was associated with increased childhood risk of deaths which is related to cancer and cardiovascular abnormalities (Rahman et al., 2013). Another study in Bangladesh showed that 1.4–60% of cardiovascular mortalities can be attributable to arsenic concentration over 12 ␮g/L in well-water, especially among smokers (Chen et al., 2011). Also, Among the South Asians, Bangladeshis, chronic arsenic exposure (>500 mg/L) in drinking water has been related to increased risks of coronary artery disease and carotid atherosclerosis which are associated with higher morbidity and mortality (Monwarul Islam and Majumder, 2013). In a cross-sectional study of blood pressure using data from 10,910 participants in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, there was a positive association between low-to-moderate levels of arsenic exposure from drinking water and high pulse pressure (pulse pressure ≥55 mm Hg), which is associated with an increased risk of atherosclerosis (Srivastava et al., 2009). James et al. study showed that there was an association between coronary heart disease and chronic low-level arsenic exposure in drinking water (below 10 ␮g/L) between Colorado residents (James et al., 2014). In Chile, high exposure to arsenic-contaminated drinking water (200–800 ␮g/L) increased the mortality because of myocardial infarction (Alissa and Ferns, 2011). Statistical analysis was done during 2005–2010 to compare the causes of death in five villages, situated in Turkey, where different arsenic levels were detected in well-water. Interestingly, 44% causes of death were related to cardiovascular system diseases (Gunduz et al., 2014). In Spain, another ecological study was reported the relationship between arsenic in public water supply and cardiovascular mortality. This study found an increased risk of coronary heart disease and stroke with average levels of arsenic of 1–10 ␮g/L (Medrano et al., 2010). 3. Mechanisms of As-induced cardiotoxicity The possible cardiotoxicity mechanisms of arsenic which include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels (Chang et al., 2007; Zhao et al., 2008a,b,c; Muthumani and Prabu, 2013) have been shown in Fig. 3. 3.1. Oxidative stress Several studies confirmed the generation of various types of ROS such as superoxide anion radical (O2 −• ), singlet oxygen (O2 ), peroxyl radical (ROO• ) and hydrogen peroxide (H2 O2 ) during arsenic metabolism in cell. Also, it mediates formation of dimethylarsinic radicals [(CH3 )2 As• ], dimethylarsinic peroxyl radicals [(CH3 )2 AsOO• ] and nitric oxide (NO• ) (Yamanaka and Okada, 1994; Volkano et al., 2005). GSH is one of the most powerful and effective cellular antioxidant which is a good marker of oxidative stress. Multiple studies

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Fig. 1. The possible sources of human arsenic exposure.

3.2. Apoptosis

Fig. 2. Natural and industrial sources of arsenic.

have reported that arsenic exposure decreases GSH level especially the cardiac glutathione (Chen et al., 1998; Jomova and Valko, 2011). It also decreases total thiol contents and increases the levels of oxidized glutathione (GSSG), DNA damage, lipid peroxidation and protein carbonyl content (Ratnaike, 2003; Manna et al., 2008; Jomova and Valko, 2011). Several investigations have provided experimental evidence that arsenic binds to the SH-group of GSH or proteins with high cysteine content which may lead to accumulation of ROS (Pulido and Parrish, 2003; Ficker et al., 2004; Raghu and Cherian, 2009; Raghu et al., 2009). Generation of ROS induced by arsenic has a central role in cardiac damage (Das et al., 2010; Muthumani and Prabu, 2013). Excess generation of ROS and cytosolic calcium accumulation play major roles in the initiation of programmed cell death during acute myocardial infarction (Webster, 2012). ROS scavengers and antioxidants (ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), glutathione (GSH), carotenoids, flavonoids and antioxidant enzymes such as glutathione reductase, glutathione peroxidase and glutathione S-transferase) could provide a possible approach to treat arsenic-mediated heart injuries (Zhao et al., 2008a,b,c; Wang et al., 2013). Although multiple studies support the role of free radicalmediated oxidative damage in the arsenic-induced organ injury and cell death, there are very little evidences about the mechanisms of arsenic-induced cardiac disorders (Alissa and Ferns, 2011).

Apoptosis is a programmed cell death in which the specific signaling pathways are activated. These pathways are tightly controlled. Morphologically, apoptotic cells are characterized by shrinkage of cell, nuclear condensation, aggregation of chromatin, DNA degradation and membrane blebbing (Savill, 2000). Although apoptotic process is not completely defined, important regulatory mechanisms include death receptors, caspases, mitochondria, bcl-2 and tumor-suppressor genes. There are two important apoptotic pathways: extrinsic and intrinsic. It is interesting to note that in metal induced apoptosis, the intrinsic pathway mediated by mitochondria is the most important (Ferri and Kroemer, 2001). Apoptosis induced by arsenic depends on cell type, time and concentration of exposure. When arsenic concentrations reach 0.5–2.0 ␮mol/L, apoptosis is triggered by several mechanisms (Hoffman et al., 2015). Importantly, ROS-mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic-induced apoptosis (Chen et al., 1998). 3.2.1. ROS-mitochondrial disruption and caspase activation The intrinsic pathway plays a pivotal role in cellular homeostasis. Arsenic exposure significantly activates cascade of caspase, especially caspase 3. Accumulation of ROS mediated by arsenic disrupts mitochondrial membrane and releases the cytochrome c which binds to APAF-1 and activates caspases. In fact, arsenic induces the opening of permeability transition pores by acting as a thiol-oxidizing agent which initiates apoptosis (Pulido and Parrish, 2003). Another study confirmed the hypothesis that arsenite induces apoptosis by a direct effect on the mitochondrial permeability pore which has a key role in the control of apoptosis. Bcl-2 antagonizes the arsenite effect because it has PT pore-inhibitory function. This indicates that the PT pore is under the direct regulatory control of antiapoptotic members of the Bcl-2 family and suggests that PT pore opening is necessary for triggering apoptosis (Larochette et al., 1999). As2 O3 exposure to H9C2 (rat cardiomyocytes cell line) induces apoptosis in clinically relevant concentrations and induces necrosis in high concentrations. As2 O3 -induced H9C2 apoptosis are associated with ROS

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Fig. 3. The possible mechanism of As-induced cardiotoxicity.

formation, caspase 3 activation and overload of intracellular calcium. Although the activation of caspases seems to play an important role in arsenic-induced apoptosis, further studies need to be performed to explain the exact role of caspases in this process (Vineetha et al., 2013) 3.2.2. MAPK signaling MAP kinases are a group of signaling regulatory proteins that control cell differentiation, cell proliferation, embryogenesis and cell death. The important MAP kinases include ERK1 [p44] and ERK2 [p42], JNK and p38. They have two phosphoacceptor sites, tyrosine and threonine which are phosphorylated to activate the kinases (Pearson et al., 2001). ERK are involved in cellular responses such as cell proliferation and survival (Chambon et al., 2007; Banerjee et al., 2011), whereas JNK and p38 are involved in proapoptotic events (Xia et al., 1995; Park et al., 2008). Many recent studies have shown that the MAPK pathway is incorporated into cardiomyocytes apoptosis (Xia et al., 1995; Ghosh et al., 2009; Fan et al., 2013). Likewise, the activation of these protein kinases can trigger apoptosis via arsenic-induced oxidative stress in cardiac tissues (Pulido and Parrish, 2003). 3.3. Changes in cardiac ion channels 3.3.1. Potassium channels Arsenic trioxide offers an effective and successful treatment in patients with relapse or refractory acute promyelocytic leukemia (Chen et al., 2010; Fan et al., 2013). Despite its effectiveness, As2 O3 has major limitations such as T wave changes, QT prolongation, Torsade depoint’s and sudden death in humans (Kumazaki et al., 2011; Wang et al., 2013).

It inhibits potassium current and induces LQTS (Zhao et al., 2008a,b,c). Blockade of hERG (potassium channels) by some medicines, for example, quinidine, moxifloxacin, terfenadine and arsenic trioxide can lead to proarrhythmia (Mumford et al., 2007). Some pathological conditions in cardiac diseases might be related to potassium function and density alterations (Chen et al., 2010). As2 O3 treatment of guinea pigs caused substantial interstitial cardiac fibrosis and LQTS because TGF-␤1 secretion increased while protein levels of delayed rectifying potassium channels such as (Ikr) subunit hERG, (IKS) subunit KvLGT1 and inward rectifying potassium channel (Ik1) subunit Kir2.1 decreased. TGF-␤1 is a multi-functional cytokine which mediates the signaling pathway to regulate matrix deposition and collagen production during the improvement of cardiac fibrosis. ATO induces cardiac fibrosis because it increases TGF-␤1 secretion leading to adverse cardiac electrical events. Consequently, modulation of TGF-␤1 signaling may provide a novel strategy for the treatment of ATO-induced long QT syndrome (Chu et al., 2012)

3.3.2. L-type calcium channels L-type calcium channels in myocardium play a vital role in the regulation of intracellular calcium. When [Ca+2 ]i increase in cardiac tissue it can lead to variety of abnormalities including ventricular arrhythmias and contractile dysfunctions (Ficker et al., 2004; Chen et al., 2010). Many studies have reported that increasing in the generation of ROS increases calcium concentration and finally causes apoptosis (Raghu and Cherian, 2009; Raghu et al., 2009). It is reported that arsenic trioxide induces down- regulation of Ik1 (Inward rectifier potassium current) and up-regulation of ICa, L (Ltype calcium current) which both might be involved in the long QT syndrome (Chen et al., 2010).

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Fig. 4. The possible mechanisms of As-induced atherosclerosis.

3.4. Changes in endothelial function Higher prevalence of ischemic heart diseases, hypertension, atherosclerosis and type 2 diabetes mellitus were found in arseniasis-hyperendemic areas (Stea et al., 2014). A study has listed variety of cardiovascular adverse effects caused by arsenic exposure such as Blackfoot disease, peripheral vascular disorders and ischemic heart disease (Tseng, 2008). There was a dose–response relation between arsenic exposure and IHD among the populations living in arseniasis-hyperendemic villages in Taiwan (Tseng et al., 2003). Another study in Taiwan has demonstrated that IHD mortality reduced after a switch in the tap-water supply system (Chang et al., 2004). Based on a cohort study of 263 patients affected with Blackfoot disease, a unique arsenic-related peripheral vascular disease, in 60 villages of arseniasis-hyperendemic areas in Taiwan, BFD patients were found to have a significantly higher IHD mortality than non-BFD residents (Chen et al., 1996). In an arsenic endemic region, West Bengal, a case control study has demonstrated that a dose-effect relationship was seen with increasing arsenic level in hair and IHD (Mazumder et al., 2013). VED, a marker of atherosclerotic risk, is often associated with various chronic disorders such as atherosclerosis, hypertension, heart failure and diabetic nephropathy. The administration of sodium arsenite (1.5 mg/kg i.p., 2 weeks) in rats markedly produced VED by diminishing the integrity of vascular endothelium. Chronic exposure to arsenic stimulates abnormalities in expression of cardiac genes which may lead to ischemic heart disease.

Arsenic may induce atherosclerosis directly by increasing mRNA transcripts of growth factors such as GMCSF, TGF␣ and the inflammatory cytokines like tumor necrosis factor-a and interleukin-6. Moreover, arsenic increases the levels of intracellular oxidized glutathione (GSSG) in endothelial cells to induce oxidative stress which may induce atherosclerosis. In addition, the activations of NF-␬B were increased in mice and human aortic endothelial cells exposed to arsenic (20 or 100 ␮g/ml sodium arsenite in drinking water for 24 weeks). Importantly, arsenic exposure enhances the aggregation of platelets and increases plasminogen activator inhibitor type-1 (PAI-1) expression and thus leading to reduced fibrinolysis (Balakumar and Kaur, 2009). The possible mechanisms involved in the pathogenesis of As-induced atherosclerosis have been depicted in Fig. 4. Several epidemiological studies suggest exposure to correlates with endothelial dysfunction and increased incidence of atherosclerosis. However, very little is known about the biochemical mechanisms by which arsenic exerts its proatherogenic effects. Genetically altered mice are preferred models to study atherogenesis. Due to the high levels of high density lipoproteins, wild-type mice are resistant to atherosclerosis (Srivastava et al., 2009). Hsieh et al. study suggests that As-induced inflammation could be an important risk factor for atherosclerosis (Hsieh et al., 2008). Short term exposure to arsenic can modulate endothelial and vascular function. Inorganic arsenic stimulates NADPH oxidase activity leading to EDHF (endothelium derived hyperpolarizing factor) type relaxations and promotes the formation of H2 O2 . NADPH oxidase can potentially reduce the generation and

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bioavailability of NO. Therefore, relaxations mediated by NO are unaffected (Edwards et al., 2013). Chronic arsenic exposure from drinking water can cause low to moderate levels of vascular inflammation and endothelial dysfunction by affecting on cardiovascular markers such as plasminogen activator inhibitor-1, myeloperoxidase, soluble vascular adhesion molecule-1 (VCAM-1) and soluble intercellular adhesion molecule-1 (ICAM-1). These adverse effects lead to cardiovascular diseases (Wu et al., 2012). Due to a study on situation of relaxation of blood vessels after arsenite exposure, dysfunction in relaxation was occurred by inactivating the eNOS in endothelial cells (Lee et al., 2003). Tsou et al. demonstrated that arsenite decreased the protein levels of AKT1 and eNOS via increased levels of ubiquitination of total cell lysates. The effect of arsenite on AKT1 and eNOS showed its involvement in cytotoxicity of vascular endothelial cells. On the other hand, this study indicated that protection of eNOS by inhibitory compound for ubiquitination can attenuate arsenite-induced cytoxicity (Tsou et al., 2005). 4. Clinical presentations and arsenic detoxification 4.1. Acute poisoning Arsenic is absorbed through all ways of entry including oral, inhalational and cutaneous routes. After absorption it is redistributed to the liver, lungs, intestinal wall, heart and spleen (Saha et al., 1999; Mittala et al., 2014). Exposure to high doses of soluble inorganic arsenic may occur many symptoms including gastrointestinal signs, change in cardiopulmonary system, central nerve system disorders and cardiovascular adverse effects (Hoffman et al., 2015). Intravenous arsenic infusion at clinical doses in the treatment of acute promyelocytic leukemia may be significantly or even fatally toxic in susceptible patients, and a few sudden deaths have been reported (Westervelt et al., 2001). In the acute arsenic cardiotoxicity, QT prolongation, T-wave changes, ST segment depression, multifocal ventricular tachycardia and myocarditis occur in clinical practice (Weinberg, 1960; RahnamaMoghadam et al., 2014). For monitoring of exposure, analyses of blood, urine and hair are used. The lethal dose of acute exposure ranges from 100 to 300 mg (Ratnaike, 2003). Definitive diagnosis of arsenic exposure hinges on finding a 24-h urinary concentration equal to or greater than 50 ␮g/L, 100 ␮g/g creatinine, or 100 ␮g total arsenic (Hoffman et al., 2015). Hair analysis is frequently used to document time of arsenic exposure. Arsenic circulating in the blood will bind to proteins with sulfhydryl groups of the amino acid cysteine. Because arsenic has high affinity for keratin, which has high cysteine content. The arsenic concentration in hair or nails is higher than in other tissue (Burtis et al., 2008). In hair sample, 1.0–3.0 mg/kg indicates acute poisoning (Ratnaike, 2003). Abnormal serum arsenic concentrations are detected for less than 4 h after ingestion. This test is useful only to document an acute exposure when the arsenic is likely to be greater than 100 ng/mL for a short period of time. Normally, the serum concentration of arsenic is less than 35 ng/mL (Burtis et al., 2008). Detoxification of acute arsenic poisoning is based on appropriate gut decontamination, supportive care and urgent chelation with unithiol, 3–5 mg/kg every 4–6 h intravenous injection or ␣,␤-dithiol 2,3dimercapto-1-propanol (dimercaprol or British Anti-Lewisite, BAL) as an antidote, 3–5 mg/kg intramuscularly every 4–6 h (Katzung et al., 2012; Ioannou et al., 2013).

changes appear as a raindrop pattern of hyperpigmentation and hyperkeratosis involving the hands and feet. After many years of exposure, various types of cancer may happen (Ratnaike, 2003; Katzung et al., 2012). There are reports of its significant association to liver, prostate, and bladder cancer. While the carcinogenicity of arsenic has been confirmed, the precise mechanisms behind the diseases occurring after acute or chronic arsenic exposure are not well understood (Hong et al., 2014). A study suggested that chronic arsenic poisoning increases risk of mortality because of myocardial injury, cardiac arrhythmias and cardiomyopathy (Ratnaike, 2003; Kumazaki et al., 2011). Long-term exposure to arsenic can lead to vitamin A deficiency, night blindness and cardiovascular effects include QT prolongation, pericarditis, IHD, hypertension and carotid atherosclerosis (Gowda et al., 2014; Nordberg et al., 2014). Importantly, IHD and carotid atherosclerosis were significantly associated with QTc intervals in chronic arsenic exposure. The mechanism of QT prolongation in Long-term exposure might be a complex process, because (1) arsenic itself may induce QT prolongation related to cardiac ion channels, and (2) it may also be related to coronary atherosclerosis or ischemic heart disease, a known contributing factor to QT prolongation (Wang et al., 2009). Lee et al. study also reported that long-term intake of arsenic in drinking water can increase thrombocyte agglutination and induce cardiovascular diseases (Lee et al., 2002). In a study of 41 cases of arsenic-induced peripheral neuropathy, most patients with a neuropathy of 4–8 weeks duration had total 24-h urinary arsenic measurements of 100–400 ␮g (Hoffman et al., 2015). Chelator therapy has not proven effective in relieving symptoms of chronic symptoms (Rahman et al., 2001; Liu et al., 2002). Primary termination of exposure with nonspecific supportive care and using folate as a cofactor in arsenic methylation might be of value in arsenic-exposed individuals (Katzung et al., 2012). However, effective treatment of chronic arsenic toxicity is not yet established (Ratnaike, 2003). The best strategy for preventing chronic arsenic poisoning is by reducing exposure (Klaassen, 2013). 5. Role of medicinal plants against As cardiac adverse effects A list of some valuable medicinal plants has been mentioned in Table 1. 5.1. Boerhavia diffusa B. diffusa is an Asian green leafy vegetable used for the treatment of jaundice, inflammation, edema and hypertension in traditional medicine. It contains large number of compounds such as flavonoids, alkaloids (punarnavine), amino acids, saponins, lignans, eupalitin 3-O-␤-d-galactopyranoside (5,4-dihydroxy 6,7dimethoxy-flavonal-3-O-␤-d-galactopyranoside), eupalitin and eupalitin 3-O-␤-d-galactopyranoside (1>2)-␤-d-glucopyranoside (Pandey et al., 2005; Agrawal et al., 2011). Some studies have demonstrated that ethanolic extract of BDE is a potent antioxidant because of rich polyphenol sources (Kumazaki et al., 2011). In Vineetha et al. study, for assessment of As-induced cytotoxicity, MTT and NR uptake assay were done. Also, in this study intracellular ROS, activities of antioxidant enzymes and [Ca+2 ]I overload were detected. It has reported that BDE has cardioprotection effect against ATO-induced toxicity (Vineetha et al., 2013). 5.2. Corchorus olitorius

4.2. Chronic poisoning Chronic absorption of inorganic arsenic is associated with various symptoms including anemia, sensorimotor peripheral neuropathy, peripheral vascular disorders and respiratory disease. Skin

C. olitorius (jute) is grown in Taiwan during summer and its tender leaves are used as a vegetable (Yan et al., 2013). This plant is one of the major products in India and Bangladesh, areas with arsenic contamination. The leaves of this popular seasonal

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Table 1 Specific properties of cardioprotective medicinal plants against ATO toxicity. Scientific name

Family name

Medicinal part

Active ingredient

B. diffusa (Punarnava)

Nyctaginaceae

Leave

S. marianum (Milk thistle)

Asteraceae

S. miltiorrhiza (Danshen)

Lamiaceae

Chemical structure

Specific Properties

Reference

Polyphenols

(-) Lactate dehydrogenase (-) Oxidative stress (-) Calcium influx (-) Organelle damage

(Vineetha et al., 2013)

Seed

Silibinin

Recovered: Serum cardiac markers Oxidative stress markers Cardiac lipid profile Mitochondrial enzymes Enzymatic antioxidant nonenzymatic antioxidants Membrane-bound ATPases Myocardial NADPH oxidase sub units

(Muthumani and Prabu, 2013)

Root

Salvanoic acid

(+) Cardiac function (+)Cardiomyocytic structure (-) Release of cardiac enzymes in serum (+) Bcl-2 and p-Akt expression (+) Cytotoxicity and apoptosis in in vitro (+) Apoptotic marker (-) Procaspase-3 expressions

(Wang et al., 2013)

Danshensu

C. olitorius (Jute)

Malvaceae

Leave

Specific polyphenols (flavone)

(-) Oxidative impairment (-) Hyperlipidemia (-) Cardiac arsenic content (-) DNA fragmentation

(Das et al., 2010)

T. arjuna (Arjuna)

Combretaceae

Bark

Arjunolic acid

(-)oxidative stress

(Manna et al., 2008)

vegetable have ethnomedicinal significance as tonic, diuretic and febrifuge (Abu-Hadid et al., 1994). It contains natural antioxidants namely flavonoids, carotenoids, vitamin C and glycosides (Azuma et al., 1999a, 1999b). Its phenolic compounds are much higher than many other vegetables (Velioglu et al., 1998).

Serum markers such as LDL, HDL and tissue markers including antioxidant enzymes namely SOD, CAT, GST, GPX and GR related to cardiac dysfunction were estimated in a study. The results showed that polyphenols and flavonoids in this plant have cardioprotective properties against As-induced toxicity (Das et al., 2010).

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5.3. Salvia miltiorrhiza S. miltiorrhiza (Danshen in Chinese) is a traditional herbal medicine for the treatment of various diseases such as hyperlipidemia, diabetic vascular complication, hepatitis, dysmenorrhea and renal failure (Li, 1998; Zhou et al., 2005, 2006; Cheng, 2007). The formulas derived from this herb like commercial Fufang Danshen are used for the treatment of heart disorders (Zhou et al., 2006; Zhao et al., 2008a,b,c). Lipophilic diterpenoid tanshinones and watersoluble phenolic acids are the two important active components in Danshen. Twenty-five phenolic acid compounds have been isolated and identified from this species of which SalB (lithospermate acid B) and Danshensu (3-(3, 4-dihydroxyphenyl) lactic acid) have the highest contents (Hu et al., 2005). It is believed that the antioxidant activity of Sal B and danshensu are related to their phenolic group. They are good free radical scavengers (Jiang et al., 2005; Zhao et al., 2008a,b,c). SalB protected cardiomyocytes from apoptosis, inhibited poly (ADP-ribose) polymerase-1 pathway and improved the integrity of mitochondrial and nucleus of heart tissue during acute myocardial infarction (AMI) (Xu et al., 2011). In a phytotherapy study, echocardiography, MTT assay, flow cytometry and western blotting on heart tissue and cancerous cells were done. The results showed that ATO induces apoptosis in both cancer and cardiac cells, but combination of SalB and ATO could provide both cancer cell toxicity and cardiac cell protection. In fact, Sal B-ATO combination therapy can provide greater toxicity to cancer cell lines (Wang et al., 2013).

responsible for its inotropic effects, while the flavonoids/phenolics such as Arjunolic Acid (AA) may provide antioxidant activity, thereby confirming the multiple activities of this medicinal plant for its cardioprotective role especially on arsenic. (Sumitra et al., 2001; Liu et al., 2002; Tsou et al., 2005; Dwivedi, 2007). 6. Conclusion Arsenic is a trace metalloid found in the environment. Many people are chronically exposed to arsenic contamination. Arsenic toxicity is well documented as it seriously affects human health. Cardiotoxicity is an important consideration in the evaluation of As2 O3 , because myocardial damage might be irreversible and lethal. Medicinal plants may serve as a source of useful new compounds for the development of effective therapy to combat cardiotoxicity in As2 O3 exposed patients. Transparency document The Transparency document associated with this article can be found in the online version. Conflict of interest The authors declare that there is no conflict of interest. Acknowledgments

5.4. Silibum marianum S. marianum (milk thistle) contains a polyphenolic flavonoid called SB which has beneficial properties on heart and other organs such as liver and brain (Muthumani and Prabu, 2013). It is predominantly found in silymarin and isolated from the seeds or fruits of milk thistle. SB has membrane stabilizing, anti-inflammatory, antioxidant and RNA, protein synthesis-stimulating properties (Mira et al., 1994). Several investigations have shown that antioxidant agents can attenuate As-induced cardiotoxicity (Abu-Hadid et al., 1994; Azuma et al., 1999a; Yan et al., 2013). Arsenic exposure may alter lipid metabolism and cause cardiac disorders. SB seems to protect against oxidative stress via decreasing the lipid peroxidation in liver microsomes and isolated hepatocytes (Bosisio et al., 1992). Furthermore, its antioxidant activity is associated with the scavenging of free radicals (De Groot and Rauen, 1998; Trouillas et al., 2008) via increasing cellular GSH content (Valenzuela et al., 1989) and superoxide dismutase levels (Müzes et al., 1991). Muthumani and Prabu were considered to investigate the mechanism of As-induced cardiomyopathy and the protective role of SB by measuring the activity of cardiac markers such as CK-MB, LDH, AST, ALT, and ALP in rats. The results indicated that pre-administration of SB in arsenic-exposed rats significantly have protective effects against oxidative stress and cardiac injury. It can be as a target of Asinduced cardiotoxicity treatment (Muthumani and Prabu, 2013). 5.5. Terminalia arjuna According to recent studies, T. arjuna is an important cardioprotective agent for treating many cardiac disorders including ischemic heart disease, arrhythmia, myocardial infarction, angina and heart failure. The alcoholic extract of the TA’s bark contains a large amount of flavones, tannins, arjunic acid, arjunolic acid, arjungenin, arjunglycosides, gallic acid and phytosterols (Tripathi, 1993; Dwivedi, 1994; Miller, 1998; Packer et al., 1999; Karthikeyan et al., 2003). T. arjuna is reported to have strong hypolipidemic properties. It is believed that the saponin glycosides in this plant may be

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