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Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Protective Role of Cytochrome C Oxidase 5A (COX5A) against Mitochondrial Disorder and Oxidative Stress in VSMC Phenotypic Modulation and Neointima Formation

Author(s): Haijing Guan, Jingwen Sun, Xiuying Liang and Wenjuan Yao*

Volume 21, Issue 2, 2023

Published on: 07 April, 2023

Page: [128 - 142] Pages: 15

DOI: 10.2174/1570161121666230315142507

Price: $65


Background: The pathological role of cytochrome c oxidase 5A (COX5A) in vascular neointima formation remains unknown.

Aim: This study aims to investigate the role of COX5A on platelet-derived growth factor BB (PDGFBB)- mediated smooth muscle phenotypic modulation and neointima formation and clarify the molecular mechanisms behind this effect.

Methods: For in vitro assays, human aortic vascular smooth muscle cells (HA-VSMCs) were transfected with pcDNA3.1-COX5A and COX5A siRNA to overexpress and knockdown COX5A, respectively. Mitochondrial complex IV activity, oxygen consumption rate (OCR), H2O2 and ATP production, reactive oxygen species (ROS) generation, cell proliferation, and migration were measured. For in vivo assays, rats after balloon injury (BI) were injected with recombinant lentivirus carrying the COX5A gene. Mitochondrial COX5A expression, carotid arterial morphology, mitochondrial ultrastructure, and ROS were measured.

Results: The results showed that PDGF-BB reduced the level and altered the distribution of COX5A in mitochondria, as well as reduced complex IV activity, ATP synthesis, and OCR while increasing H2O2 synthesis, ROS production, and cell proliferation and migration. These effects were reversed by overexpression of COX5A and aggravated by COX5A knockdown. In addition, COX5A overexpression attenuated BI-induced neointima formation, muscle fiber area ratio, VSMC migration to the intima, mitochondrial ultrastructural damage, and vascular ROS generation.

Conclusion: The present study demonstrated that COX5A protects VSMCs against phenotypic modulation by improving mitochondrial respiratory function and attenuating mitochondrial damage, as well as reducing oxidative stress, thereby preventing neointima formation.

Keywords: COX5A, mitochondrial respiratory chain, VSMC phenotypic modulation, intimal hyperplasia, oxidative stress, cytochrome c.

Graphical Abstract
Wu W, Wang C, Zang H, et al. Mature vascular smooth muscle cells, but not endothelial cells, serve as the major cellular source of intimal hyperplasia in vein grafts. Arterioscler Thromb Vasc Biol 2020; 40(8): 1870-90.
[] [PMID: 32493169]
Pashova A, Work LM, Nicklin SA. The role of extracellular vesicles in neointima formation post vascular injury. Cell Signal 2020; 76: 109783.
[] [PMID: 32956789]
Yuan B, Liu H, Pan X, et al. LSD1 downregulates p21 expression in vascular smooth muscle cells and promotes neointima formation. Biochem Pharmacol 2022; 198: 114947.
[] [PMID: 35143753]
Zhu Q, Ni XQ, Lu WW, et al. Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway. Atherosclerosis 2017; 266: 212-22.
[] [PMID: 29053988]
Yang F, Chen Q, He S, et al. miR-22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation. Circulation 2018; 137(17): 1824-41.
[] [PMID: 29246895]
Sorokin V, Vickneson K, Kofidis T, et al. Role of vascular smooth muscle cell plasticity and interactions in vessel wall inflammation. Front Immunol 2020; 11: 599415.
[] [PMID: 33324416]
Yuan B, Liu H, Dong X, et al. A novel resveratrol analog upregulates SIRT1 expression and ameliorates neointima formation. Front Cardiovasc Med 2021; 8: 756098.
[] [PMID: 34796214]
Song T, Zhao J, Jiang T, Jin X, Li Y, Liu X. Formononetin protects against balloon injury-induced neointima formation in rats by regulating proliferation and migration of vascular smooth muscle cells via the TGF-β1/Smad3 signaling pathway. Int J Mol Med 2018; 42(4): 2155-62.
[] [PMID: 30066831]
Chen Y, Chen Y, Jiang X, et al. Vascular adventitial fibroblasts-derived FGF10 promotes vascular smooth muscle cells proliferation and migration in vitro and the neointima formation in vivo. J Inflamm Res 2021; 14: 2207-23.
[] [PMID: 34079328]
Lu QB, Wan MY, Wang PY, et al. Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation, proliferation and migration by suppressing ROS/NFκB/mTOR/P70S6K signaling cascade. Redox Biol 2018; 14: 656-68.
[] [PMID: 29175753]
Tang L, Dai F, Liu Y, et al. RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton. Pharmacol Res 2018; 133: 201-12.
[] [PMID: 29791873]
Qi Y, Liang X, Guan H, Sun J, Yao W. RhoGDI1-Cdc42 signaling is required for PDGF-BB-induced phenotypic transformation of vascular smooth muscle cells and neointima formation. Biomedicines 2021; 9(9): 1169.
[] [PMID: 34572355]
Merrill RA, Strack S. Mitochondria: A kinase anchoring protein 1, a signaling platform for mitochondrial form and function. Int J Biochem Cell Biol 2014; 48: 92-6.
[] [PMID: 24412345]
Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest 2018; 128(9): 3716-26.
[] [PMID: 30124471]
Dey S, DeMazumder D, Sidor A, Foster DB, O’Rourke B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res 2018; 123(3): 356-71.
[] [PMID: 29898892]
Luongo TS, Lambert JP, Gross P, et al. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature 2017; 545(7652): 93-7.
[] [PMID: 28445457]
Tian R, Colucci WS, Arany Z, et al. Unlocking the secrets of mitochondria in the cardiovascular system: path to a cure in heart failure-a report from the 2018 national heart, lung, and blood institute workshop. Circulation 2019; 140(14): 1205-16.
[] [PMID: 31769940]
Hou T, Wang X, Ma Q, Cheng H. Mitochondrial flashes: New insights into mitochondrial ROS signalling and beyond. J Physiol 2014; 592(17): 3703-13.
[] [PMID: 25038239]
Cao LL, Riascos-Bernal DF, Chinnasamy P, et al. Control of mitochondrial function and cell growth by the atypical cadherin Fat1. Nature 2016; 539(7630): 575-8.
[] [PMID: 27828948]
Oliveira HCF, Vercesi AE. Mitochondrial bioenergetics and redox dysfunctions in hypercholesterolemia and atherosclerosis. Mol Aspects Med 2020; 71: 100840.
[] [PMID: 31882067]
Gu J, Wu M, Guo R, et al. The architecture of the mammalian respirasome. Nature 2016; 537(7622): 639-43.
[] [PMID: 27654917]
Lang H, Li Q, Yu H, et al. Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function. Br J Pharmacol 2015; 172(23): 5548-58.
[] [PMID: 25339153]
Sousa JS, D’Imprima E, Vonck J. Mitochondrial respiratory chain complexes. Subcell Biochem 2018; 87: 167-227.
[] [PMID: 29464561]
Bourens M, Barrientos A. ACMC 1 ‐knockout reveals translationindependent control of human mitochondrial complex IV biogenesis. EMBO Rep 2017; 18(3): 477-94.
[] [PMID: 28082314]
Bi R, Zhang W, Zhang DF, et al. Genetic association of the cytochrome c oxidase-related genes with Alzheimer’s disease in Han Chinese. Neuropsychopharmacology 2018; 43(11): 2264-76.
[] [PMID: 30054583]
Uddin M, Opazo JC, Wildman DE, et al. Molecular evolution of the cytochrome c oxidase subunit 5 A gene in primates. BMC Evol Biol 2008; 8(1): 8.
[] [PMID: 18197981]
Baertling F, Al-Murshedi F, Sánchez-Caballero L, et al. Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. Hum Mutat 2017; 38(6): 692-703.
[] [PMID: 28247525]
Jiang Y, Bai X, Li TT, et al. COX5A over-expression protects cortical neurons from hypoxic ischemic injury in neonatal rats associated with TPI up-regulation. BMC Neurosci 2020; 21(1): 18.
[] [PMID: 32349668]
Lu H, Yang Y, Allister EM, Wijesekara N, Wheeler MB. The identification of potential factors associated with the development of type 2 diabetes: a quantitative proteomics approach. Mol Cell Proteomics 2008; 7(8): 1434-51.
[] [PMID: 18448419]
Weidberg H, Amon A. MitoCPR—A surveillance pathway that protects mitochondria in response to protein import stress. Science 2018; 360(6385): eaan4146.
[] [PMID: 29650645]
Zhang P, Chen Z, Lu D, et al. Overexpression of COX5A protects H9c2 cells against doxorubicin-induced cardiotoxicity. Biochem Biophys Res Commun 2020; 524(1): 43-9.
[] [PMID: 31980176]
Yao W, Fan W, Huang C, Zhong H, Chen X, Zhang W. Proteomic analysis for anti-atherosclerotic effect of tetrahydroxystilbene glucoside in rats. Biomed Pharmacother 2013; 67(2): 140-5.
[] [PMID: 23206751]
Fornuskova D, Stiburek L, Wenchich L, Vinsova K, Hansikova H, Zeman J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J 2010; 428(3): 363-74.
[] [PMID: 20307258]
Dunnill C, Patton T, Brennan J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J 2017; 14(1): 89-96.
[] [PMID: 26688157]
Diebold L, Chandel NS. Mitochondrial ROS regulation of proliferating cells. Free Radic Biol Med 2016; 100: 86-93.
[] [PMID: 27154978]
Jukema JW, Verschuren JJW, Ahmed TAN, Quax PHA. Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat Rev Cardiol 2012; 9(1): 53-62.
[] [PMID: 21912414]
Pérez-Gracia E, Torrejón-Escribano B, Ferrer I. Dystrophic neurites of senile plaques in Alzheimer’s disease are deficient in cytochrome c oxidase. Acta Neuropathol 2008; 116(3): 261-8.
[] [PMID: 18629521]

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