Novel Insights into the Molecular Mechanisms of Atherosclerosis
Abstract
:1. Introduction
Atherosclerosis
2. Inflammation
3. Aging
- Age increases the aortic plaque burden and the size and severity of the aortic root plaques in the AD-fed ApoE mice independent of the number of weeks on the diet. However, there was no effect from age on the size or severity of oscillatory shear-induced carotid artery atheromas after PCL.
- Treatment with PCSK9 increased the total and LDL cholesterol in the young mice, but the older mice had a larger aortic root atheroma size and morphology grade. Age did not affect the size or degree of the carotid artery lesions in the mice overexpressing PCK9 after PCL. Atherosclerotic plaques will expand spontaneously in the atheroprone regions of the aorta of the AD-fed mice after PCSK9 overexpression by an AAV. The transgenic ApoE mice also overexpressed human PCSK9, demonstrating larger atherosclerotic lesions with greater monocyte infiltration compared with the PCSK9 wildtype ApoE mice [57].
4. Endothelial Dysfunction
5. Uric Acid
6. Vitamin D
6.1. Vitamin D and Its Metabolism
6.2. Vitamin D and Its Impact on Atherosclerosis
7. miRNA Expression
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CVD | cardiovascular disease |
UA | uric acid |
Vit. D | vitamin D |
1,25(OH)2D | calcitriol, 1,25-dihydroxyvitamin D |
miRNA | microRNA |
ACS | acute coronary syndrome |
CKD | chronic kidney disease |
LDL | low-density lipoproteins |
CVDs | cardiovascular diseases |
CCs | cholesterol-soluble compounds |
NETs | neutrophil extracellular traps |
Tet2 | ten-eleven translocation 2 |
HDL | high-density lipoprotein |
oxLDLs | oxidized low-density lipoproteins |
ROS | reactive oxygen species |
TNFα | tumor necrosis factor α |
VCAM-1 | vascular cell adhesion molecule-1 |
RNS | reactive nitrogen species |
LDL-C | LDL-cholesterol |
CHIP | clonal hematopoiesis of indeterminate potential |
VSMCs | vascular smooth muscle cells |
PCSK9 | proprotein convertase subtilisin/kexin type 9 |
LDLRs | low-density lipoprotein receptors |
AAV | adeno-associated virus |
PCL | partial carotid ligation |
ACKR3 | atypical chemokine receptor 3 |
NO | nitrogen oxide |
RAAS | renin–angiotensin–aldosterone system |
AngII | angiotensin II |
XO | xanthine oxidase |
NADPH | nicotinamide adenine dinucleotide phosphate |
NRF2 | nuclear factor erythroid 2-related factor 2 |
25OHD | 25-hydroxyvitamin D |
VDR | intracellular vitamin D receptor |
RCT | randomized controlled trial |
miRNAs | microRNAs |
MRN A | messenger RNA |
Sirt1 | silent information regulator |
pHLIP | pH low-insertion peptides |
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Study | Year | Study Design | Findings |
---|---|---|---|
Polito et al. [110] | 2021 | Review article | XO plays a significant role in CVDs, including atherosclerosis, through various mechanisms such as oxidative stress, inflammation, endothelial dysfunction, and modulation of purinergic signaling. |
Kotozaki et al. [111] | 2023 | Population-based study | Higher XO activity in human plasma is associated with an increased risk of CVDs, indicating its potential role as a biomarker and a therapeutic target. |
Kimura et al. [112] | 2021 | Review article | UA contributes to the pathogenesis of atherosclerosis by promoting inflammation through the activation of immune cells, modulation of vascular function, and induction of oxidative stress. |
Yan et al. [117] | 2018 | In vitro study (cardiomyocytes) | UA induces cardiomyocyte apoptosis by activating calpain-1 and endoplasmic reticulum stress, suggesting a potential mechanism by which hyperuricemia contributes to cardiac dysfunction. |
Hu et al. [118] | 2022 | Clinical study | Elevated serum US levels are associated with a pro-inflammatory state and have an impact on the role of HDL-C in promoting carotid atherosclerosis, highlighting the link between UA, inflammation, and atherosclerosis. |
Yu et al. [119] | 2022 | Experimental study (cellular and animal models) | High levels of UA promote atherosclerosis by impairing autophagy through NRF2-mediated dysfunction and inducing ferroptosis, providing insights into the molecular mechanisms underlying the pro-atherogenic effects of UA. |
Gene | Cell/Tissue Type | Function or Association with Disease |
---|---|---|
miR-1 | blood, VSMCs | Expression is associated with subclinical atherosclerosis. Induces VSMC differentiation. |
miR-10a | serum, VSMCs | Negative regulator of SMC differentiation. |
miR-19a | ECs, B cells, VSMCs | Promotion of VSMC proliferation. Suppression of IL-10-mediated immunomodulation. Mediates the effects of laminar flow and cell cycle progression. |
miR-33a/b | Cells from liver, macrophages, fibroblasts | Regulation of cholesterol homeostasis. |
miR-146a | VSMCs, EPCs | VSMC proliferation. Neointimal hyperplasia. |
miR-302a | macrophages | Regulation of cholesterol efflux. |
miR-221 and miR-222 | VSMCs | VSMC proliferation. Neointimal hyperplasia. |
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Wojtasińska, A.; Frąk, W.; Lisińska, W.; Sapeda, N.; Młynarska, E.; Rysz, J.; Franczyk, B. Novel Insights into the Molecular Mechanisms of Atherosclerosis. Int. J. Mol. Sci. 2023, 24, 13434. https://doi.org/10.3390/ijms241713434
Wojtasińska A, Frąk W, Lisińska W, Sapeda N, Młynarska E, Rysz J, Franczyk B. Novel Insights into the Molecular Mechanisms of Atherosclerosis. International Journal of Molecular Sciences. 2023; 24(17):13434. https://doi.org/10.3390/ijms241713434
Chicago/Turabian StyleWojtasińska, Armanda, Weronika Frąk, Wiktoria Lisińska, Natalia Sapeda, Ewelina Młynarska, Jacek Rysz, and Beata Franczyk. 2023. "Novel Insights into the Molecular Mechanisms of Atherosclerosis" International Journal of Molecular Sciences 24, no. 17: 13434. https://doi.org/10.3390/ijms241713434