International Journal of Molecular Sciences

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Open AccessEditorial

Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0

by Ida Perrotta

Int. J. Mol. Sci. 2022, 23(23), 15158; https://doi.org/10.3390/ijms232315158 - 02 Dec 2022

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Abstract

Atherosclerosis is a chronic inflammatory disease of large- and medium-sized arteries involving aberrant immune–inflammatory responses, dysfunctional molecular pathways, and impaired tissue repair mechanisms [...] Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

Research

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23 pages, 3874 KiB

Open AccessArticle

Platelet SR-PSOX/CXCL16–CXCR6 Axis Influences Thrombotic Propensity and Prognosis in Coronary Artery Disease

by Tianyun Guan, Frederic Emschermann, Christoph Schories, Patrick Groga-Bada, Peter Martus, Oliver Borst, Meinrad Gawaz, Tobias Geisler, Dominik Rath and Madhumita Chatterjee

Int. J. Mol. Sci. 2022, 23(19), 11066; https://doi.org/10.3390/ijms231911066 - 21 Sep 2022

Cited by 3 | Viewed by 1570

Abstract

Platelets express the transmembrane chemokine SR-PSOX/CXCL16, proteolytic cleavage of which generates the sCXCL16 soluble-(s) chemokine. The sCXCL16 engages CXCR6 on platelets to synergistically propagate degranulation, aggregation and thrombotic response. Currently, we have investigated the pro-thrombotic and prognostic association of platelet CXCL16–CXCR6 axis in [...] Read more.

Platelets express the transmembrane chemokine SR-PSOX/CXCL16, proteolytic cleavage of which generates the sCXCL16 soluble-(s) chemokine. The sCXCL16 engages CXCR6 on platelets to synergistically propagate degranulation, aggregation and thrombotic response. Currently, we have investigated the pro-thrombotic and prognostic association of platelet CXCL16–CXCR6 axis in CAD-(n = 240; CCS n = 62; ACS n = 178) patients. Platelet surface-associated-CXCL16 and CXCR6 surface expression ascertained by flow cytometry correlated significantly with platelet activation markers (CD62P denoting degranulation and PAC-1 binding denoting α_2bβ₃-integrin activation). Higher platelet CXCL16 surface association (1st quartile vs. 2nd–4th quartiles) corresponded to significantly elevated collagen-induced platelet aggregation assessed by whole blood impedance aggregometry. Platelet-CXCL16 and CXCR6 expression did not alter with dyslipidemia, triglyceride, total cholesterol, or LDL levels, but higher (>median) plasma HDL levels corresponded with decreased platelet-CXCL16 and CXCR6. Although platelet-CXCL16 and CXCR6 expression did not change significantly with or correlate with troponin I levels, they corresponded with higher Creatine Kinase-(CK) activity and progressively deteriorating left ventricular ejection fraction (LVEF) at admission. Elevated-(4th quartile) platelet-CXCL16 (p = 0.023) and CXCR6 (p = 0.030) measured at admission were significantly associated with a worse prognosis. However, after Cox-PH regression analysis, only platelet-CXCL16 was ascertained as an independent predictor for all-cause of mortality. Therefore, the platelet CXCL16–CXCR6 axis may influence thrombotic propensity and prognosis in CAD patients. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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14 pages, 5906 KiB

Open AccessArticle

Yohimbine, an α2-Adrenoceptor Antagonist, Suppresses PDGF-BB-Stimulated Vascular Smooth Muscle Cell Proliferation by Downregulating the PLCγ1 Signaling Pathway

by Chih-Wei Chiu, Cheng-Ying Hsieh, Chih-Hao Yang, Jie-Heng Tsai, Shih-Yi Huang and Joen-Rong Sheu

Int. J. Mol. Sci. 2022, 23(14), 8049; https://doi.org/10.3390/ijms23148049 - 21 Jul 2022

Cited by 3 | Viewed by 2325

Abstract

Yohimbine (YOH) has antiproliferative effects against breast cancer and pancreatic cancer; however, its effects on vascular proliferative diseases such as atherosclerosis remain unknown. Accordingly, we investigated the inhibitory mechanisms of YOH in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF)-BB, [...] Read more.

Yohimbine (YOH) has antiproliferative effects against breast cancer and pancreatic cancer; however, its effects on vascular proliferative diseases such as atherosclerosis remain unknown. Accordingly, we investigated the inhibitory mechanisms of YOH in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF)-BB, a major mitogenic factor in vascular diseases. YOH (5–20 μM) suppressed PDGF-BB-stimulated a mouse VSMC line (MOVAS-1 cell) proliferation without inducing cytotoxicity. YOH also exhibited antimigratory effects and downregulated matrix metalloproteinase-2 and -9 expression in PDGF-BB-stimulated MOVAS-1 cells. It also promoted cell cycle arrest in the initial gap/first gap phase by upregulating p27Kip1 and p53 expression and reducing cyclin-dependent kinase 2 and proliferating cell nuclear antigen expression. We noted phospholipase C-γ1 (PLCγ1) but not ERK1/2, AKT, or p38 kinase phosphorylation attenuation in YOH-modulated PDGF-BB-propagated signaling pathways in the MOVAS-1 cells. Furthermore, YOH still inhibited PDGF-BB-induced cell proliferation and PLCγ1 phosphorylation in MOVAS-1 cells with α2B-adrenergic receptor knockdown. YOH (5 and 10 mg/kg) substantially suppressed neointimal hyperplasia in mice subjected to CCA ligation for 21 days. Overall, our results reveal that YOH attenuates PDGF-BB-stimulated VSMC proliferation and migration by downregulating a α2B-adrenergic receptor–independent PLCγ1 pathway and reduces neointimal formation in vivo. Therefore, YOH has potential for repurposing for treating atherosclerosis and other vascular proliferative diseases. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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16 pages, 1311 KiB

Open AccessArticle

Variations in the Gene Expression Profile in Atherosclerotic Patients with Non-Fatal ACS: A Preliminary Study

by Angela Dziedzic, Rafal Szelenberger, Michal Kacprzak, Piotr Czarny, Ewelina Synowiec, Joanna Saluk-Bijak, Tomasz Sliwinski, Marzenna Zielinska and Michal Bijak

Int. J. Mol. Sci. 2022, 23(9), 5017; https://doi.org/10.3390/ijms23095017 - 30 Apr 2022

Cited by 1 | Viewed by 1836

Abstract

The pathophysiology of atherosclerosis and acute coronary syndrome (ACS) is related to interactions between immune cells, endothelium, and blood platelets. An increasing number of reports confirm the link between excessive immune activation and cellular cross-talk with ACS incidence. Our genetic and proteomic analysis [...] Read more.

The pathophysiology of atherosclerosis and acute coronary syndrome (ACS) is related to interactions between immune cells, endothelium, and blood platelets. An increasing number of reports confirm the link between excessive immune activation and cellular cross-talk with ACS incidence. Our genetic and proteomic analysis was performed on strictly selected atherosclerotic patients with non-fatal ACS without typical risk factors and healthy donors. Results showed changes in the gene expression levels of the various inflammatory factors derived from the peripheral blood cells that drive the over-activation of the immune system. The enhanced activation of the immune system may lead to the overexpression of the pro-inflammatory mediators, which causes self-perpetuating machinery of processes associated with thrombosis. In our preliminary study, we confirmed an altered expression of genes associated with the inflammation and overall interaction of the vascular microenvironment. Furthermore, 5 of 92 analyzed genes, CCL2, CCR2, CSF2, GZMB, and ICOS, were expressed only in patients with ACS. In conclusion, the augmented expression of the pro-inflammatory genes from the peripheral blood cells may be a crucial genetic factor leading to the occurrence of acute inflammation and thus be significant in ACS pathogenesis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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19 pages, 7418 KiB

Open AccessArticle

Immature Vascular Smooth Muscle Cells in Healthy Murine Arteries and Atherosclerotic Plaques: Localization and Activity

by Alexander Balatskiy, Ilia Ozhimalov, Maria Balatskaya, Alexandra Savina, Julia Filatova, Natalia Kalinina, Vladimir Popov and Vsevolod Tkachuk

Int. J. Mol. Sci. 2022, 23(3), 1744; https://doi.org/10.3390/ijms23031744 - 03 Feb 2022

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Abstract

The local development of atherosclerotic lesions may, at least partly, be associated with the specific cellular composition of atherosclerosis-prone regions. Previously, it was demonstrated that a small population of immature vascular smooth muscle cells (VSMCs) expressing both CD146 and neuron-glial antigen 2 is [...] Read more.

The local development of atherosclerotic lesions may, at least partly, be associated with the specific cellular composition of atherosclerosis-prone regions. Previously, it was demonstrated that a small population of immature vascular smooth muscle cells (VSMCs) expressing both CD146 and neuron-glial antigen 2 is postnatally sustained in atherosclerosis-prone sites. We supposed that these cells may be involved in atherogenesis and can continuously respond to angiotensin II, which is an atherogenic factor. Using immunohistochemistry, flow cytometry, wound migration assay xCELLigence system, and calcium imaging, we studied the functional activities of immature VSMCs in vitro and in vivo. According to our data, these cells do not express nestin, CD105, and the leptin receptor. They are localized in atherosclerosis-prone regions, and their number increases with age, from 5.7% to 23%. Immature VSMCs do not migrate to low shear stress areas and atherosclerotic lesions. They also do not have any unique response to angiotensin II. Thus, despite the localization of immature VSMCs and the presence of the link between their number and age, our study did not support the hypothesis that immature VSMCs are directly involved in the formation of atherosclerotic lesions. Additional lineage tracing studies can clarify the fate of these cells during atherogenesis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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17 pages, 4260 KiB

Open AccessArticle

Evaluation of Oxidative Stress Biomarkers, Pro-Inflammatory Cytokines, and Histological Changes in Experimental Hypertension, Dyslipidemia, and Type 1 Diabetes Mellitus

by Paul-Mihai Boarescu, Ioana Boarescu, Raluca Maria Pop, Ştefan Horia Roşian, Ioana Corina Bocșan, Vasile Rus, Răzvan Olimpiu Mada, Iulia Diana Popa, Nicholas Neagu, Adriana Elena Bulboacă, Anca Dana Buzoianu and Sorana D. Bolboacă

Int. J. Mol. Sci. 2022, 23(3), 1438; https://doi.org/10.3390/ijms23031438 - 27 Jan 2022

Cited by 15 | Viewed by 3235

Abstract

The present study aims to compare the oxidative stress biomarkers, pro-inflammatory cytokines, and histological changes induced by three cardiovascular risk factors, namely, hypertension, dyslipidemia, and type 1 diabetes mellitus. Hypertension was induced with 40 mg/kg body weight (b.w.) of N omega-nitro-L-arginine-methyl (L-NAME) administered [...] Read more.

The present study aims to compare the oxidative stress biomarkers, pro-inflammatory cytokines, and histological changes induced by three cardiovascular risk factors, namely, hypertension, dyslipidemia, and type 1 diabetes mellitus. Hypertension was induced with 40 mg/kg body weight (b.w.) of N omega-nitro-L-arginine-methyl (L-NAME) administered orally. Dyslipidemia was induced by the administration of a diet with a high cholesterol (2%) content. Diabetes mellitus was induced by intraperitoneal administration of a single dose of streptozocin (65 mg/kg). Malondialdehyde (MDA) and total oxidative status (TOS) are increased by all three cardiovascular risk factors (up to 207%). The indirect assessment of NO synthesis (NOx) is observed to be reduced after L-NAME administration (43%), and dyslipidemia induction (16%), while type 1 diabetes mellitus is associated with the highest levels of NOx (increased 112%). Hypertension, dyslipidemia, and type 1 diabetes reduced the total antioxidative capacity (TAC) and total thiol (SH) levels (up to 57%). The values of evaluated pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), assessed from the ascending aorta were elevated by all three cardiovascular risk factors, with the highest levels induced by type 1 diabetes mellitus (up to 259%). The histopathological examination of the ascending and descending aorta revealed reversible pro-atherogenic changes consisting of the accumulation of lipid droplets in the subendothelial connective tissue on rats with hypertension and dyslipidemia. Irreversible pro-atherogenic changes consisting of a reduction of the specific elasticity of the arteries were observed in rats with type 1 diabetes mellitus. Type 1 diabetes mellitus demonstrates an alteration of the oxidative stress parameters, the elevation of tissue levels of the pro-inflammatory cytokines and causing irreversible pro-atherogenic changes on the aortic wall. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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33 pages, 11588 KiB

Open AccessArticle

Calciprotein Particles Link Disturbed Mineral Homeostasis with Cardiovascular Disease by Causing Endothelial Dysfunction and Vascular Inflammation

by Daria K. Shishkova, Elena A. Velikanova, Leo A. Bogdanov, Maxim Yu. Sinitsky, Alexander E. Kostyunin, Anna V. Tsepokina, Olga V. Gruzdeva, Andrey V. Mironov, Rinat A. Mukhamadiyarov, Tatiana V. Glushkova, Evgenia O. Krivkina, Vera G. Matveeva, Oksana N. Hryachkova, Victoria E. Markova, Yulia A. Dyleva, Ekaterina V. Belik, Alexey V. Frolov, Amin R. Shabaev, Olga S. Efimova, Anna N. Popova, Valentina Yu. Malysheva, Roman P. Kolmykov, Oleg G. Sevostyanov, Dmitriy M. Russakov, Viatcheslav F. Dolganyuk, Anton K. Gutakovsky, Yuriy A. Zhivodkov, Anton S. Kozhukhov, Elena B. Brusina, Zinfer R. Ismagilov, Olga L. Barbarash, Arseniy E. Yuzhalin and Anton G. Kutikhin Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12458; https://doi.org/10.3390/ijms222212458 - 18 Nov 2021

Cited by 10 | Viewed by 2441

Abstract

An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium [...] Read more.

An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca²⁺-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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Review

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24 pages, 1189 KiB

Open AccessReview

Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk

by Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima and Hisayuki Katsuyama

Int. J. Mol. Sci. 2022, 23(21), 13499; https://doi.org/10.3390/ijms232113499 - 04 Nov 2022

Cited by 13 | Viewed by 2786

Abstract

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect [...] Read more.

Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56–79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78–87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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14 pages, 975 KiB

Open AccessReview

CaMKII Splice Variants in Vascular Smooth Muscle Cells: The Next Step or Redundancy?

by Finn T. Roberts-Craig, Luke P. Worthington, Samuel P. O’Hara, Jeffrey R. Erickson, Alison K. Heather and Zoe Ashley

Int. J. Mol. Sci. 2022, 23(14), 7916; https://doi.org/10.3390/ijms23147916 - 18 Jul 2022

Cited by 4 | Viewed by 2067

Abstract

Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca²⁺/calmodulin-dependent kinase II (CaMKII), a multifunctional enzyme with four isoforms and multiple [...] Read more.

Vascular smooth muscle cells (VSMCs) help to maintain the normal physiological contractility of arterial vessels to control blood pressure; they can also contribute to vascular disease such as atherosclerosis. Ca²⁺/calmodulin-dependent kinase II (CaMKII), a multifunctional enzyme with four isoforms and multiple alternative splice variants, contributes to numerous functions within VSMCs. The role of these isoforms has been widely studied across numerous tissue types; however, their functions are still largely unknown within the vasculature. Even more understudied is the role of the different splice variants of each isoform in such signaling pathways. This review evaluates the role of the different CaMKII splice variants in vascular pathological and physiological mechanisms, aiming to show the need for more research to highlight both the deleterious and protective functions of the various splice variants. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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17 pages, 1420 KiB

Open AccessReview

Advanced Glycation End Products: A Sweet Flavor That Embitters Cardiovascular Disease

by Raphael S. Pinto, Carlos A. Minanni, Aécio Lopes de Araújo Lira and Marisa Passarelli

Int. J. Mol. Sci. 2022, 23(5), 2404; https://doi.org/10.3390/ijms23052404 - 22 Feb 2022

Cited by 14 | Viewed by 5543

Abstract

Epidemiological studies demonstrate the role of early and intensive glycemic control in the prevention of micro and macrovascular disease in both type 1 and type 2 diabetes mellitus (DM). Hyperglycemia elicits several pathways related to the etiopathogenesis of cardiovascular disease (CVD), including the [...] Read more.

Epidemiological studies demonstrate the role of early and intensive glycemic control in the prevention of micro and macrovascular disease in both type 1 and type 2 diabetes mellitus (DM). Hyperglycemia elicits several pathways related to the etiopathogenesis of cardiovascular disease (CVD), including the generation of advanced glycation end products (AGEs). In this review, we revisit the role played by AGEs in CVD based in clinical trials and experimental evidence. Mechanistic aspects concerning the recognition of AGEs by the advanced glycosylation end product-specific receptor (AGER) and its counterpart, the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST) and soluble AGER are discussed. A special focus is offered to the AGE-elicited pathways that promote cholesterol accumulation in the arterial wall by enhanced oxidative stress, inflammation, endoplasmic reticulum stress and impairment in the reverse cholesterol transport (RCT). Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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19 pages, 1273 KiB

Open AccessReview

Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis

by Milijana Janjusevic, Alessandra Lucia Fluca, Giulia Gagno, Alessandro Pierri, Laura Padoan, Annamaria Sorrentino, Antonio Paolo Beltrami, Gianfranco Sinagra and Aneta Aleksova

Int. J. Mol. Sci. 2022, 23(4), 2336; https://doi.org/10.3390/ijms23042336 - 20 Feb 2022

Cited by 4 | Viewed by 3103

Abstract

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists [...] Read more.

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD). Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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26 pages, 1700 KiB

Open AccessReview

Involvement of Fatty Acids and Their Metabolites in the Development of Inflammation in Atherosclerosis

by Stanislav Kotlyarov and Anna Kotlyarova

Int. J. Mol. Sci. 2022, 23(3), 1308; https://doi.org/10.3390/ijms23031308 - 24 Jan 2022

Cited by 23 | Viewed by 5090

Abstract

Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is [...] Read more.

Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is associated with the accumulation of lipids in the arterial intima and the disruption of mechanisms that maintain the balance between the development and resolution of inflammation. Fatty acids are involved in many mechanisms of inflammation development and maintenance. Endothelial cells demonstrate multiple cross-linkages between lipid metabolism and innate immunity. In addition, these processes are linked to hemodynamics and the function of other cells in the vascular wall, highlighting the central role of the endothelium in vascular biology. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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13 pages, 1497 KiB

Open AccessReview

Exosome-Based Treatment for Atherosclerosis

by Jeongyeon Heo and Hara Kang

Int. J. Mol. Sci. 2022, 23(2), 1002; https://doi.org/10.3390/ijms23021002 - 17 Jan 2022

Cited by 35 | Viewed by 5583

Abstract

Atherosclerosis is an inflammatory disease in which lipids accumulate on the walls of blood vessels, thickening and clogging these vessels. It is well known that cell-to-cell communication is involved in the pathogenesis of atherosclerosis. Exosomes are extracellular vesicles that deliver various substances (e.g., [...] Read more.

Atherosclerosis is an inflammatory disease in which lipids accumulate on the walls of blood vessels, thickening and clogging these vessels. It is well known that cell-to-cell communication is involved in the pathogenesis of atherosclerosis. Exosomes are extracellular vesicles that deliver various substances (e.g., RNA, DNA, and proteins) from the donor cell to the recipient cell and that play an important role in intercellular communication. Atherosclerosis can be either induced or inhibited through cell-to-cell communication using exosomes. An understanding of the function of exosomes as therapeutic tools and in the pathogenesis of atherosclerosis is necessary to develop new atherosclerosis therapies. In this review, we summarize the studies on the regulation of atherosclerosis through exosomes derived from multiple cells as well as research on exosome-based atherosclerosis treatment. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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26 pages, 3061 KiB

Open AccessReview

Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging

by Elena Barbu, Mihaela-Roxana Popescu, Andreea-Catarina Popescu and Serban-Mihai Balanescu

Int. J. Mol. Sci. 2022, 23(2), 963; https://doi.org/10.3390/ijms23020963 - 16 Jan 2022

Cited by 33 | Viewed by 4783

Abstract

Vascular disease was for a long time considered a disease of the old age, but it is becoming increasingly clear that a cumulus of factors can cause early vascular aging (EVA). Inflammation plays a key role in vascular stiffening and also in other [...] Read more.

Vascular disease was for a long time considered a disease of the old age, but it is becoming increasingly clear that a cumulus of factors can cause early vascular aging (EVA). Inflammation plays a key role in vascular stiffening and also in other pathologies that induce vascular damage. There is a known and confirmed connection between inflammation and atherosclerosis. However, it has taken a long time to prove the beneficial effects of anti-inflammatory drugs on cardiovascular events. Diabetes can be both a product of inflammation and a cofactor implicated in the progression of vascular disease. When diabetes and inflammation are accompanied by obesity, this ominous trifecta leads to an increased incidence of atherothrombotic events. Research into earlier stages of vascular disease, and documentation of vulnerability to premature vascular disease, might be the key to success in preventing clinical events. Modulation of inflammation, combined with strict control of classical cardiovascular risk factors, seems to be the winning recipe. Identification of population subsets with a successful vascular aging (supernormal vascular aging—SUPERNOVA) pattern could also bring forth novel therapeutic interventions. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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18 pages, 1371 KiB

Open AccessReview

Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing

by Siarhei A. Dabravolski, Vasily N. Sukhorukov, Vladislav A. Kalmykov, Nikolay A. Orekhov, Andrey V. Grechko and Alexander N. Orekhov

Int. J. Mol. Sci. 2022, 23(2), 649; https://doi.org/10.3390/ijms23020649 - 07 Jan 2022

Cited by 11 | Viewed by 2961

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of misfolded proteins, thus supporting the high metabolic demand of the heart cells. Heat shock protein 90 (HSP90) is one of the main cardioprotective chaperones, represented by cytosolic HSP90a and HSP90b, mitochondrial TRAP1 and ER-localised Grp94 isoforms. Currently, the main way to study the functional role of HSPs is the application of HSP inhibitors, which could have a different way of action. In this review, we discussed the recently investigated role of HSP90 proteins in cardioprotection, atherosclerosis, CVDs development and the involvements of HSP90 clients in the activation of different molecular pathways and signalling mechanisms, related to heart ageing. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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17 pages, 1043 KiB

Open AccessReview

Inflammation in Coronary Microvascular Dysfunction

by Marios Sagris, Panagiotis Theofilis, Alexios S. Antonopoulos, Evangelos Oikonomou, Christina Paschaliori, Nikolaos Galiatsatos, Kostas Tsioufis and Dimitris Tousoulis

Int. J. Mol. Sci. 2021, 22(24), 13471; https://doi.org/10.3390/ijms222413471 - 15 Dec 2021

Cited by 43 | Viewed by 5239

Abstract

Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 μm, whose potential structural and [...] Read more.

Chronic low-grade inflammation is involved in coronary atherosclerosis, presenting multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, heart failure and sudden cardiac death. Coronary microvasculature consists of vessels with a diameter less than 500 μm, whose potential structural and functional abnormalities can lead to inappropriate dilatation and an inability to meet the required myocardium oxygen demands. This review focuses on the pathogenesis of coronary microvascular dysfunction and the capability of non-invasive screening methods to detect the phenomenon. Anti-inflammatory agents, such as statins and immunomodulators, including anakinra, tocilizumab, and tumor necrosis factor-alpha inhibitors, have been assessed recently and may constitute additional or alternative treatment approaches to reduce cardiovascular events in atherosclerotic heart disease characterized by coronary microvascular dysfunction. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective 2.0)

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