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Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque
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Heart, Lung and Circulation (2019) xx, 1–6 1443-9506/04/$36.00 https://doi.org/10.1016/j.hlc.2019.04.022
Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque Zhongqun Wang, PhD a*1, Lili Zhang, MSc a,1, Zhen Sun, MSc a, Chen Shao, PhD a, Yukun Li, MSc a, Zhengyang Bao, MSc a, Lele Jing, MSc a, Yue Geng, MSc a, Wen Gu, MSc a, Qiwen Pang, MSc a, Lihua Li, MSc b*, Jinchuan Yan, PhD a* a
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
b
Received 19 January 2019; received in revised form 6 April 2019; accepted 22 April 2019; online published-ahead-of-print xxx
Vascular calcification is a key character of advanced plaque in diabetic atherosclerosis. Microcalcification induces plaque rupture, whereas macrocalcification contributes to plaque stability. However, there is still no clear explanation for the formation and transition of these two types of calcification. Based on existing work and the latest international progress, this article provides a brief review of four aspects: calcification transition in plaque; matrix vesicle-mediated calcification transition in plaque; regulation mechanism of matrix vesicle-mediated calcification transition in diabetic plaque; and proposal of a new hypothesis, which may offer a new perspective on the study of the mechanism of calcification transition in plaque. Keywords
Advanced glycation end products Matrix vesicles Vascular calcification Calcification transition Atherosclerosis
Diabetes mellitus (DM) is severely harmful to human health. A whopping 387 million people worldwide have diabetes, and someone dies of diabetes every 7 seconds [1]. Of all the complications of death and disability in diabetes, the formation of calcification in atherosclerotic plaque is a main risk factor of advanced adverse events, which can not only bring about a 1.5-times increased mortality and a 5.5-times increased amputation rate, but also play a major role in the malignant evolution of acute myocardial infarction (MI) or acute left heart failure [2]. Recent studies have shown that different forms and sizes of calcification in plaques induce different clinical transitions: microcalcification (diameter <200 mm) promotes plaque rupture and subsequent formation of acute MI; macrocalcification (diameter 200 mm) stabilises plaque, reduces vascular wall compliance, and promotes the development of heart failure [3–6]. However, the existing research cannot accurately answer
how the two types of calcification in the plaque are formed, and what the mechanism of the transition is.
Transition of Plaque Calcification Vascular calcification refers to the phenotypic transdifferentiation of osteo-/chondroblasts in mesenchymal cells like smooth muscle cells (SMCs) under pathological conditions such as atherosclerosis, diabetes, and chronic kidney disease secreting matrix vesicles and locally absorbing and accumulating calcium and phosphate to form hydroxyapatite crystals [7]. The process is highly similar to bone formation occurring in valves, veins, and the intima and media of the arteries [8]. The molecular mechanism of vascular calcification is related to the dynamic balance between calcification inhibitors and calcification-promoting factors.
*Corresponding authors at: Department of Cardiology, Affiliated Hospital of Jiangsu University, Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China., Emails: [email protected], [email protected], [email protected] 1
Contributed equally to this work.
© 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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Calcification inhibitors (e.g. matrix Gla protein; pyrophosphate; fetuin-A; osteopontin; Klotho; osteoprotegerin) are reduced, and the level of calcification-related promoting factors (e.g. bone morphogenetic protein/receptor activator of nuclear factor kappa-B ligand, etc.) is increased, and the imbalance between the two increases susceptibility to vascular calcification [9]. As a serious hazard to human health, calcification in plaques, or intimal calcification, is most important for the occurrence of cardiovascular adverse events. There are four main viewpoints on calcification in plaque [8,10–13]: (1) apoptotic bodies and necrotic debris released by macrophages and SMCs provide nucleating sites for calcium phosphate crystal formation; (2) bone remodelling releases circulating nucleation complexes or SMCs/macrophages release matrix vesicles (MVs) [14], which are the starting sites for amorphous calcium phosphate crystal nucleation; (3) when the concentration of phosphates regulated by alkaline phosphatase reaches enough nucleation concentration, minerals in MVs are formed and deposited in the osteogenic collagen fibres; (4) reducing the level of circulation and tissue-derived calcification inhibitor can promote apatite deposition (formed by the re-organisation of amorphous calcium phosphate) and differentiate SMCs into osteoblast-like cells, which can consequently foster the formation of calcification [15,16]. Although these views demonstrate causes and development of vascular calcification from different aspects, there are still many unsolved mysteries in the origin of micro- and macrocalcification and the mechanism of their transition. With the development of microdissection, nanoparticle analysis, high-resolution light electron microscopy, and a variety of new staining techniques, as the current study suggests, MVs in atherosclerotic plaques are a common source of micro- and macrocalcification, which play a key role in the formation of microcalcification and its mutual transformation with macrocalcification [4,17].
Matrix Vesicles Mediate the Transition of Plaque Calcification Matrix vesicles are a kind of membrane microparticle located in the extracellular matrix with a diameter of 30–300 nm [18]. Current studies have confirmed that MVs are released from the mineral-forming cells or vascular SMCs (VSMCs) undergoing phenotypic differentiation to the extracellular matrix via the process of budding, and interact with extracellular matrix proteins, causing a large influx of Ca2+ into MVs, providing the material basis for apatite crystallisation, and initiating the mineralisation or ectopic calcification process [4,17,19–22]. The formation of microcalcification and that of macrocalcification during MV aggregation and fusion are two key processes in plaque calcification. Previous studies have shown that spot-like microcalcification, especially microcalcification on the fibrous cap, produces a ‘‘grinding-like effect” with the contraction of blood vessels, and
continuously cuts the fibrous cap, causing plaque rupture, thus inducing thrombosis, subsequent MI, amputation, and other cardiovascular events [3–6,23,24]. Therefore, microcalcification of MVs is a ‘‘culprit” in which plaque vulnerability increases and instability occurs. Under the influence of various regulatory factors, MVs further aggregate and fuse to form microcalcification, increase plaque stability, form an armour-like structure, and reduce plaque rupture [24]. Measurements using the finite element mathematical model show that MV-derived microcalcification in the fibre cap increases the circumferential stress of the fibre cap to 600 kPa, far exceeding the critical threshold (300 kPa) required for fibre cap rupture [25,26]. This provides the best evidence for the aggregation and fusion of MVs to form calcium deposit nucleus, leading to microcalcification formation and plaque rupture. Further, three-dimensional collagen hydrogel and multimodal imaging studies suggest that the nucleation and growth of SMC-derived MVs comprise the following stages [4]: (1) single MV aggregation; (2) multiple MV enrichment; (3) MV fusion; (4) minerals mature and microcalcifications form. When not affected by collagen and inflammation, microcalcification can act as a precursor for the formation of large calcifications. Aortic plaque microcalcification occurred in apolipoprotein E-deficient (apoE–/–) mice injected with two calcium tracers after 20 weeks of being fed a high-fat diet, evolving into macrocalcification after 23 weeks [4]. These studies suggest that MV release/enrichment, and micro- and macrocalcification formation are three typical stages of atherosclerotic plaque calcification transition. However, in diabetic atherosclerosis, what mechanism initiates and regulates the release and enrichment of MVs in the plaque and leads to the formation and transition of microand macrocalcification? Existing research is not yet able to give a clear answer.
Regulation Mechanism of Matrix Vesicle-Mediated Diabetic Plaque Calcification Transition Role of Advanced Glycation End Products in the Formation of Calcification in Diabetic Plaque Advanced glycation end products (AGEs) are the most important metabolites of diabetic glucose toxicity, which participate in multiple stages of diabetic cardiovascular complications [1,27,28]. Our previous study found that Ne-carboxymethyl-lysine (CML), a key component of serum AGEs, can be seen as an early indicator for the calcification of anterior tibial artery plaque in patients with diabetic amputation [29]. Further, our research group successfully replicated the animal and cell model of calcification in diabetic plaque using CML [30], finding that the calcification of the anterior tibial artery plaque in patients with diabetic foot amputation showed the appearance of focal microcalcification [31]. In addition, our research group previously
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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synthesised the CML fluorine-18 (18F)-labelled tracer, and carried out a pharmacokinetic study of the novel molecular probe under physiological and pathological conditions [32]. The findings suggest that the 18F-labelled molecular probe based on CML could effectively trace atherosclerotic plaque in diabetes and its specificity and sensitivity are higher than that of 18F-fluorodeoxyglucose [33–35]. Based on this, with the help of 18F-CML receptor imaging, various new types of calcification stain and the newly developed 18F-NaF micropositron emission tomography/high-resolution micro-computed tomography scanning technology (sensitive and specific differentiation between micro- and macrocalcification) [36], we can explore CML’s mechanism of receptor-mediated calcification formation and transition more completely from different aspects.
Role of Advanced Glycosylation End Product Receptors in Matrix VesicleMediated Calcification Diabetic Plaque Calcification It is known that AGEs have two major receptors in atherosclerotic plaque: receptor for advanced glycation end products (RAGE) and galectin-3 (Gal-3) [27,31,37,38]. Mainly distributed in microcalcifications and unstable plaques caused by inflammation, RAGE, a membrane receptor with a transmembrane domain, is mostly found in inflammatory infiltrating mononuclear macrophages and SMCs [39]. Differently from the distribution of RAGE, gal-3 is mainly expressed in macrocalcification, non-inflammatory plaques, and areas of VSMC fibrosis, which can be distributed in the circulation, extracellular matrix and nucleus, plasma, and membranes, but it lacks in transmembrane domain and is rarely seen in areas of inflammatory vulnerable plaques and microcalcifications [9,31,37,38]. In vitro studies have shown that blocking Gal-3 is associated with a decrease in the diameter of SMC extracellular matrix calcified nodules and an increase in the number of nodules [24]. Our previous study of diabetic apoE–/– mice also confirmed that calcifications formed in plaques after silencing of Gal-3 by short hairpin RNA (shRNA) changed from macrocalcification to microcalcification, and blocking Gal-3 significantly up-regulated the expression of RAGE; further isolation of MVs in plaques revealed that the aggregation and fusion ability of MVs in the Gal-3 blocking group was weakened, and the ability of aggregation and fusion of MVs in the RAGE blocking group were significantly enhanced; MVs isolated from the plaque were used to interfere with aortic SMCs cultured in calcified medium. The changes in the distribution of extracellular matrix calcification after 14 days were consistent with the results in vivo, which indicate that blocking RAGE promotes the formation of large amounts of calcification and blocking Gal-3 promotes the appearance of microcalcification. The distribution of extracellular matrix calcifications after 14 days was consistent with consistent with the in vivo results; in other words, blocking RAGE promoted the formation of macrocalcification and blocking
Gal-3 promoted microcalcification [24]. Comprehensive studies have shown that RAGE/Gal-3, the two major receptors of glycosylation end products, may play a completely opposite role in the formation and transition of MV-derived calcification [37–44]. However, it remains unclear how RAGE/Gal-3 regulates the release and enrichment of MVs and then forms two different types of calcifications.
Sortilin Functions as a Molecular Switch in the Regulation of Vesicle-Mediated Diabetic Plaque Calcification by RAGE According to the latest data, sortilin can promote the transition of microcalcification to macrocalcification by regulating the release of MVs from SMCs and inducing their enrichment and fusion in the extracellular matrix [45,46]. Sortilin and caveolin-1 constitute a protein complex to recruit calcified protein tissue non-specific alkaline phosphatase (TNAP) into MVs. Tissue non-specific alkaline phosphatase then hydrolyses pyrophosphate (which inhibits calcification) to phosphate (which promotes calcification), and the hydrolysed phosphate combines with calcium ions enriched in MVs to form calcium phosphate, which finally forms bone-specific apatite crystals through recombination [47,48]. Silencing SMC with sortilin using shRNA technology can reduce TNAP-mediated calcification of MVs to 45%, and overexpression of sortilin increases MVs TNAP activity twice [49]. In the pre-experiment, successfully constructed viral expression vectors of RAGE shRNA and Gal-3 shRNA were injected into diabetic apoE–/– mice fed with a high-fat diet via tail vein. After 20 weeks of intervention, it was found that Gal-3 shRNA down-regulated the expression of sortilin, decreased the enrichment and fusion ability of MVs in plaques, and significantly increased micro-calcifications in plaques. In contrast, RAGE shRNA up-regulated the expression of sortilin and enhanced the ability of aggregation and fusion of MVs in plaques, and macrocalcification in plaques increased significantly [24]. Combined with the latest developments [48,49], we speculate that sortilin may be a ‘‘molecular switch” that regulates the release of MVs by RAGE/Gal-3 and mediates the transformation of macro- and microcalcification in diabetic atherosclerotic plaque. Then, does RAGE/Gal-3 mediate the activity of sortilin through a certain signal, or affect the release and enrichment of MVs, as well as calcification outcome via the target molecule bound to scaffolding region of the sortilin–caveolin-1 protein complex? Existing research has not yet been able to answer this question. What is known is that AGEs bind to their intratissue receptors and mediate the evolution of diabetic vascular calcification mainly through transforming growth factor (TGF)-b, mitogen-activated protein kinase (MAPK), Akt, and nuclear factor kappa B (NF-kB) pathways [50–53]. Our previous studies suggested that the AGE CML binds to RAGE and mediates microcalcification in diabetic atherosclerotic plaque via the p38/MAPK pathway [31]. Does RAGE/Gal-3 induce changes in the scaffolding effector molecule of sortilin and its protein complex via the TGF-b,
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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Figure 1 Diagram of our current working hypothesis of the role of matrix vesicles (MVs) mediating the transition of calcification in plaque. (A) Carboxymethyl-lysine (CML) binds to receptor for advanced glycation end products (RAGE)/galectin-3 (Gal-3) and induces the change of sortilin through transforming growth factor (TGF)-b, mitogen-activated protein kinase (MAPK), Akt, and nuclear factor kappa B (NF-kB) pathways, which regulates the release and enrichment of MVs to mediate the transition of calcification and leads to diabetic mellitus atherosclerosis (DM AS) progression. (B) MVs are released from vascular smooth muscle cells (VSMC) to the extracellular matrix by budding, and interact with the extracellular matrix proteins, causing a large amount of Ca2+/Pi to flow into the MVs, providing a material basis for the hydroxyapatite crystals to form microcalcification. Under the influence of various regulatory factors, MVs are further aggregated and fused to form large calcification. Abbreviations: ApoE–/–, apolipoprotein deficient; LDLR–/–, low density lipoprotein receptor deficient.
MAPK, Akt, and NF-kB pathways, leading to the release and enrichment of MV, as well as transition of micro- and macrocalcification? The confirmation of involvement of these specific signalling pathways, and the mechanisms for selection and activation of one or more pathways, needs careful further study.
Proposal and Prospect of the New Hypothesis Based on the research progress that has been made in this field and the experimental results of our research group, we put forward the hypothesis that RAGE/Gal-3 regulates the
release and enrichment of MVs by triggering the molecular switch sortilin to mediate calcification transition in plaques (as shown in Figure 1). With the help of high-resolution micro-computed tomography, new molecular probe micropositron emission tomography radionuclide imaging, and multiple pathological morphological staining and molecular biology techniques, we use apoE–/– mice and low-density lipoprotein receptor deficient (LDLR–/–) hamster model animals, common two-dimensional cell culture, and a threedimensional collagen hydrogel cell culture vector to explore the temporal and spatial characteristics of MVs, and microand macrocalcifications of the aorta and coronary arteries. Moreover, we clarify the RAGE/Gal-3 regulatory mechanism of MVs mediating the transition of calcification in
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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diabetic atherosclerotic plaque. These findings will provide a more comprehensive experimental basis for further study of the mechanism of calcification transition in diabetic plaque, and will also bring new entry points for calcification prevention strategies targeting pathogenesis.
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Conflicts of Interest
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There are no conflicts of interest to disclose.
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Disclosure This work was supported as follows: the National Natural Science Foundation of China (grant numbers 81770450, 81370408, 81670405); the Foundation of Jiangsu Province (WSN-044, LGY2018092, QNRC2016836), the Open Program of Key Laboratory of Nuclear Medicine, Ministry of Health and Jiangsu Key Laboratory of Molecular Nuclear Medicine (KF201504); and Graduate Student Scientific Research Innovation Projects of Jiangsu Province (SJCX18_0754, KYCX17_1801).
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REVIEW
Heart, Lung and Circulation (2019) xx, 1–6 1443-9506/04/$36.00 https://doi.org/10.1016/j.hlc.2019.04.022
Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque Zhongqun Wang, PhD a*1, Lili Zhang, MSc a,1, Zhen Sun, MSc a, Chen Shao, PhD a, Yukun Li, MSc a, Zhengyang Bao, MSc a, Lele Jing, MSc a, Yue Geng, MSc a, Wen Gu, MSc a, Qiwen Pang, MSc a, Lihua Li, MSc b*, Jinchuan Yan, PhD a* a
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
b
Received 19 January 2019; received in revised form 6 April 2019; accepted 22 April 2019; online published-ahead-of-print xxx
Vascular calcification is a key character of advanced plaque in diabetic atherosclerosis. Microcalcification induces plaque rupture, whereas macrocalcification contributes to plaque stability. However, there is still no clear explanation for the formation and transition of these two types of calcification. Based on existing work and the latest international progress, this article provides a brief review of four aspects: calcification transition in plaque; matrix vesicle-mediated calcification transition in plaque; regulation mechanism of matrix vesicle-mediated calcification transition in diabetic plaque; and proposal of a new hypothesis, which may offer a new perspective on the study of the mechanism of calcification transition in plaque. Keywords
Advanced glycation end products Matrix vesicles Vascular calcification Calcification transition Atherosclerosis
Diabetes mellitus (DM) is severely harmful to human health. A whopping 387 million people worldwide have diabetes, and someone dies of diabetes every 7 seconds [1]. Of all the complications of death and disability in diabetes, the formation of calcification in atherosclerotic plaque is a main risk factor of advanced adverse events, which can not only bring about a 1.5-times increased mortality and a 5.5-times increased amputation rate, but also play a major role in the malignant evolution of acute myocardial infarction (MI) or acute left heart failure [2]. Recent studies have shown that different forms and sizes of calcification in plaques induce different clinical transitions: microcalcification (diameter <200 mm) promotes plaque rupture and subsequent formation of acute MI; macrocalcification (diameter 200 mm) stabilises plaque, reduces vascular wall compliance, and promotes the development of heart failure [3–6]. However, the existing research cannot accurately answer
how the two types of calcification in the plaque are formed, and what the mechanism of the transition is.
Transition of Plaque Calcification Vascular calcification refers to the phenotypic transdifferentiation of osteo-/chondroblasts in mesenchymal cells like smooth muscle cells (SMCs) under pathological conditions such as atherosclerosis, diabetes, and chronic kidney disease secreting matrix vesicles and locally absorbing and accumulating calcium and phosphate to form hydroxyapatite crystals [7]. The process is highly similar to bone formation occurring in valves, veins, and the intima and media of the arteries [8]. The molecular mechanism of vascular calcification is related to the dynamic balance between calcification inhibitors and calcification-promoting factors.
*Corresponding authors at: Department of Cardiology, Affiliated Hospital of Jiangsu University, Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China., Emails: [email protected], [email protected], [email protected] 1
Contributed equally to this work.
© 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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Calcification inhibitors (e.g. matrix Gla protein; pyrophosphate; fetuin-A; osteopontin; Klotho; osteoprotegerin) are reduced, and the level of calcification-related promoting factors (e.g. bone morphogenetic protein/receptor activator of nuclear factor kappa-B ligand, etc.) is increased, and the imbalance between the two increases susceptibility to vascular calcification [9]. As a serious hazard to human health, calcification in plaques, or intimal calcification, is most important for the occurrence of cardiovascular adverse events. There are four main viewpoints on calcification in plaque [8,10–13]: (1) apoptotic bodies and necrotic debris released by macrophages and SMCs provide nucleating sites for calcium phosphate crystal formation; (2) bone remodelling releases circulating nucleation complexes or SMCs/macrophages release matrix vesicles (MVs) [14], which are the starting sites for amorphous calcium phosphate crystal nucleation; (3) when the concentration of phosphates regulated by alkaline phosphatase reaches enough nucleation concentration, minerals in MVs are formed and deposited in the osteogenic collagen fibres; (4) reducing the level of circulation and tissue-derived calcification inhibitor can promote apatite deposition (formed by the re-organisation of amorphous calcium phosphate) and differentiate SMCs into osteoblast-like cells, which can consequently foster the formation of calcification [15,16]. Although these views demonstrate causes and development of vascular calcification from different aspects, there are still many unsolved mysteries in the origin of micro- and macrocalcification and the mechanism of their transition. With the development of microdissection, nanoparticle analysis, high-resolution light electron microscopy, and a variety of new staining techniques, as the current study suggests, MVs in atherosclerotic plaques are a common source of micro- and macrocalcification, which play a key role in the formation of microcalcification and its mutual transformation with macrocalcification [4,17].
Matrix Vesicles Mediate the Transition of Plaque Calcification Matrix vesicles are a kind of membrane microparticle located in the extracellular matrix with a diameter of 30–300 nm [18]. Current studies have confirmed that MVs are released from the mineral-forming cells or vascular SMCs (VSMCs) undergoing phenotypic differentiation to the extracellular matrix via the process of budding, and interact with extracellular matrix proteins, causing a large influx of Ca2+ into MVs, providing the material basis for apatite crystallisation, and initiating the mineralisation or ectopic calcification process [4,17,19–22]. The formation of microcalcification and that of macrocalcification during MV aggregation and fusion are two key processes in plaque calcification. Previous studies have shown that spot-like microcalcification, especially microcalcification on the fibrous cap, produces a ‘‘grinding-like effect” with the contraction of blood vessels, and
continuously cuts the fibrous cap, causing plaque rupture, thus inducing thrombosis, subsequent MI, amputation, and other cardiovascular events [3–6,23,24]. Therefore, microcalcification of MVs is a ‘‘culprit” in which plaque vulnerability increases and instability occurs. Under the influence of various regulatory factors, MVs further aggregate and fuse to form microcalcification, increase plaque stability, form an armour-like structure, and reduce plaque rupture [24]. Measurements using the finite element mathematical model show that MV-derived microcalcification in the fibre cap increases the circumferential stress of the fibre cap to 600 kPa, far exceeding the critical threshold (300 kPa) required for fibre cap rupture [25,26]. This provides the best evidence for the aggregation and fusion of MVs to form calcium deposit nucleus, leading to microcalcification formation and plaque rupture. Further, three-dimensional collagen hydrogel and multimodal imaging studies suggest that the nucleation and growth of SMC-derived MVs comprise the following stages [4]: (1) single MV aggregation; (2) multiple MV enrichment; (3) MV fusion; (4) minerals mature and microcalcifications form. When not affected by collagen and inflammation, microcalcification can act as a precursor for the formation of large calcifications. Aortic plaque microcalcification occurred in apolipoprotein E-deficient (apoE–/–) mice injected with two calcium tracers after 20 weeks of being fed a high-fat diet, evolving into macrocalcification after 23 weeks [4]. These studies suggest that MV release/enrichment, and micro- and macrocalcification formation are three typical stages of atherosclerotic plaque calcification transition. However, in diabetic atherosclerosis, what mechanism initiates and regulates the release and enrichment of MVs in the plaque and leads to the formation and transition of microand macrocalcification? Existing research is not yet able to give a clear answer.
Regulation Mechanism of Matrix Vesicle-Mediated Diabetic Plaque Calcification Transition Role of Advanced Glycation End Products in the Formation of Calcification in Diabetic Plaque Advanced glycation end products (AGEs) are the most important metabolites of diabetic glucose toxicity, which participate in multiple stages of diabetic cardiovascular complications [1,27,28]. Our previous study found that Ne-carboxymethyl-lysine (CML), a key component of serum AGEs, can be seen as an early indicator for the calcification of anterior tibial artery plaque in patients with diabetic amputation [29]. Further, our research group successfully replicated the animal and cell model of calcification in diabetic plaque using CML [30], finding that the calcification of the anterior tibial artery plaque in patients with diabetic foot amputation showed the appearance of focal microcalcification [31]. In addition, our research group previously
Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022
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synthesised the CML fluorine-18 (18F)-labelled tracer, and carried out a pharmacokinetic study of the novel molecular probe under physiological and pathological conditions [32]. The findings suggest that the 18F-labelled molecular probe based on CML could effectively trace atherosclerotic plaque in diabetes and its specificity and sensitivity are higher than that of 18F-fluorodeoxyglucose [33–35]. Based on this, with the help of 18F-CML receptor imaging, various new types of calcification stain and the newly developed 18F-NaF micropositron emission tomography/high-resolution micro-computed tomography scanning technology (sensitive and specific differentiation between micro- and macrocalcification) [36], we can explore CML’s mechanism of receptor-mediated calcification formation and transition more completely from different aspects.
Role of Advanced Glycosylation End Product Receptors in Matrix VesicleMediated Calcification Diabetic Plaque Calcification It is known that AGEs have two major receptors in atherosclerotic plaque: receptor for advanced glycation end products (RAGE) and galectin-3 (Gal-3) [27,31,37,38]. Mainly distributed in microcalcifications and unstable plaques caused by inflammation, RAGE, a membrane receptor with a transmembrane domain, is mostly found in inflammatory infiltrating mononuclear macrophages and SMCs [39]. Differently from the distribution of RAGE, gal-3 is mainly expressed in macrocalcification, non-inflammatory plaques, and areas of VSMC fibrosis, which can be distributed in the circulation, extracellular matrix and nucleus, plasma, and membranes, but it lacks in transmembrane domain and is rarely seen in areas of inflammatory vulnerable plaques and microcalcifications [9,31,37,38]. In vitro studies have shown that blocking Gal-3 is associated with a decrease in the diameter of SMC extracellular matrix calcified nodules and an increase in the number of nodules [24]. Our previous study of diabetic apoE–/– mice also confirmed that calcifications formed in plaques after silencing of Gal-3 by short hairpin RNA (shRNA) changed from macrocalcification to microcalcification, and blocking Gal-3 significantly up-regulated the expression of RAGE; further isolation of MVs in plaques revealed that the aggregation and fusion ability of MVs in the Gal-3 blocking group was weakened, and the ability of aggregation and fusion of MVs in the RAGE blocking group were significantly enhanced; MVs isolated from the plaque were used to interfere with aortic SMCs cultured in calcified medium. The changes in the distribution of extracellular matrix calcification after 14 days were consistent with the results in vivo, which indicate that blocking RAGE promotes the formation of large amounts of calcification and blocking Gal-3 promotes the appearance of microcalcification. The distribution of extracellular matrix calcifications after 14 days was consistent with consistent with the in vivo results; in other words, blocking RAGE promoted the formation of macrocalcification and blocking
Gal-3 promoted microcalcification [24]. Comprehensive studies have shown that RAGE/Gal-3, the two major receptors of glycosylation end products, may play a completely opposite role in the formation and transition of MV-derived calcification [37–44]. However, it remains unclear how RAGE/Gal-3 regulates the release and enrichment of MVs and then forms two different types of calcifications.
Sortilin Functions as a Molecular Switch in the Regulation of Vesicle-Mediated Diabetic Plaque Calcification by RAGE According to the latest data, sortilin can promote the transition of microcalcification to macrocalcification by regulating the release of MVs from SMCs and inducing their enrichment and fusion in the extracellular matrix [45,46]. Sortilin and caveolin-1 constitute a protein complex to recruit calcified protein tissue non-specific alkaline phosphatase (TNAP) into MVs. Tissue non-specific alkaline phosphatase then hydrolyses pyrophosphate (which inhibits calcification) to phosphate (which promotes calcification), and the hydrolysed phosphate combines with calcium ions enriched in MVs to form calcium phosphate, which finally forms bone-specific apatite crystals through recombination [47,48]. Silencing SMC with sortilin using shRNA technology can reduce TNAP-mediated calcification of MVs to 45%, and overexpression of sortilin increases MVs TNAP activity twice [49]. In the pre-experiment, successfully constructed viral expression vectors of RAGE shRNA and Gal-3 shRNA were injected into diabetic apoE–/– mice fed with a high-fat diet via tail vein. After 20 weeks of intervention, it was found that Gal-3 shRNA down-regulated the expression of sortilin, decreased the enrichment and fusion ability of MVs in plaques, and significantly increased micro-calcifications in plaques. In contrast, RAGE shRNA up-regulated the expression of sortilin and enhanced the ability of aggregation and fusion of MVs in plaques, and macrocalcification in plaques increased significantly [24]. Combined with the latest developments [48,49], we speculate that sortilin may be a ‘‘molecular switch” that regulates the release of MVs by RAGE/Gal-3 and mediates the transformation of macro- and microcalcification in diabetic atherosclerotic plaque. Then, does RAGE/Gal-3 mediate the activity of sortilin through a certain signal, or affect the release and enrichment of MVs, as well as calcification outcome via the target molecule bound to scaffolding region of the sortilin–caveolin-1 protein complex? Existing research has not yet been able to answer this question. What is known is that AGEs bind to their intratissue receptors and mediate the evolution of diabetic vascular calcification mainly through transforming growth factor (TGF)-b, mitogen-activated protein kinase (MAPK), Akt, and nuclear factor kappa B (NF-kB) pathways [50–53]. Our previous studies suggested that the AGE CML binds to RAGE and mediates microcalcification in diabetic atherosclerotic plaque via the p38/MAPK pathway [31]. Does RAGE/Gal-3 induce changes in the scaffolding effector molecule of sortilin and its protein complex via the TGF-b,
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Figure 1 Diagram of our current working hypothesis of the role of matrix vesicles (MVs) mediating the transition of calcification in plaque. (A) Carboxymethyl-lysine (CML) binds to receptor for advanced glycation end products (RAGE)/galectin-3 (Gal-3) and induces the change of sortilin through transforming growth factor (TGF)-b, mitogen-activated protein kinase (MAPK), Akt, and nuclear factor kappa B (NF-kB) pathways, which regulates the release and enrichment of MVs to mediate the transition of calcification and leads to diabetic mellitus atherosclerosis (DM AS) progression. (B) MVs are released from vascular smooth muscle cells (VSMC) to the extracellular matrix by budding, and interact with the extracellular matrix proteins, causing a large amount of Ca2+/Pi to flow into the MVs, providing a material basis for the hydroxyapatite crystals to form microcalcification. Under the influence of various regulatory factors, MVs are further aggregated and fused to form large calcification. Abbreviations: ApoE–/–, apolipoprotein deficient; LDLR–/–, low density lipoprotein receptor deficient.
MAPK, Akt, and NF-kB pathways, leading to the release and enrichment of MV, as well as transition of micro- and macrocalcification? The confirmation of involvement of these specific signalling pathways, and the mechanisms for selection and activation of one or more pathways, needs careful further study.
Proposal and Prospect of the New Hypothesis Based on the research progress that has been made in this field and the experimental results of our research group, we put forward the hypothesis that RAGE/Gal-3 regulates the
release and enrichment of MVs by triggering the molecular switch sortilin to mediate calcification transition in plaques (as shown in Figure 1). With the help of high-resolution micro-computed tomography, new molecular probe micropositron emission tomography radionuclide imaging, and multiple pathological morphological staining and molecular biology techniques, we use apoE–/– mice and low-density lipoprotein receptor deficient (LDLR–/–) hamster model animals, common two-dimensional cell culture, and a threedimensional collagen hydrogel cell culture vector to explore the temporal and spatial characteristics of MVs, and microand macrocalcifications of the aorta and coronary arteries. Moreover, we clarify the RAGE/Gal-3 regulatory mechanism of MVs mediating the transition of calcification in
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diabetic atherosclerotic plaque. These findings will provide a more comprehensive experimental basis for further study of the mechanism of calcification transition in diabetic plaque, and will also bring new entry points for calcification prevention strategies targeting pathogenesis.
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Conflicts of Interest
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There are no conflicts of interest to disclose.
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Disclosure This work was supported as follows: the National Natural Science Foundation of China (grant numbers 81770450, 81370408, 81670405); the Foundation of Jiangsu Province (WSN-044, LGY2018092, QNRC2016836), the Open Program of Key Laboratory of Nuclear Medicine, Ministry of Health and Jiangsu Key Laboratory of Molecular Nuclear Medicine (KF201504); and Graduate Student Scientific Research Innovation Projects of Jiangsu Province (SJCX18_0754, KYCX17_1801).
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Please cite this article in press as: Wang Z, et al. Mechanisms of Matrix Vesicles Mediating Calcification Transition in Diabetic Plaque. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.04.022