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Published online: 2024-05-13

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Integrin subunit alpha 5 maintains mitochondrial function in ox-LDL-induced cardiac microvascular endothelial cells via activating the PI3K/AKT signaling pathway

Xianfeng Wang1, Wenkai Mao2, Xiaofeng Ma3
Pubmed: 38757500

Abstract

Cardiac microvascular endothelial cells (CMECs) assume a pivotal role in the regulation of blood flow, and their impairment precipitates a spectrum of pathological transformations. Our previous study unveiled a notable mitigation of CMECs dysfunction through the intervention of integrin subunit alpha 5 (ITGA5), a member of the integrin protein family. This study delves into the effect of ITGA5 on the mitochondrial function in CMECs and reveals the regulation pathway. CMECs were stimulated with oxidized low-density lipoprotein (ox-LDL) to mimic coronary artery disease (CAD). The effects of ITGA5 on diverse facets of CMEC behavior, encompassing viability, apoptosis, angiogenesis, oxidative stress, and mitochondrial function, was systematically ascertained. Employing the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway as a focal point of investigation, the mediation of this pathway was substantiated utilizing the PI3K inhibitor LY294002. ITGA5 overexpression exerted a mitigating influence upon the ox-LDL-induced detriment to CMECs, manifested as increased viability, angiogenesis, mitochondrial function, and diminished apoptosis and oxidative stress. The counteraction of these salubrious effects by the administration of the PI3K inhibitor attests to the engagement of the PI3K/AKT signaling pathway. Overall, this study has discerned that ITGA5 activates the PI3k/Akt signaling pathway to orchestrate mitochondrial function and diminish ox-LDL-induced CMEC dysfunction. Thus, the targeted amelioration of this cellular injury emerges as a strategically pivotal endeavor for the prevention and amelioration of this ailment.

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References

  1. Chen G, Xu C, Gillette TG, et al. Cardiomyocyte-derived small extracellular vesicles can signal eNOS activation in cardiac microvascular endothelial cells to protect against Ischemia/Reperfusion injury. Theranostics. 2020; 10(25): 11754–11774.
  2. Deng J. Research progress on the molecular mechanism of coronary microvascular endothelial cell dysfunction. Int J Cardiol Heart Vasc. 2021; 34: 100777.
  3. Finney AC, Stokes KY, Pattillo CB, et al. Integrin signaling in atherosclerosis. Cell Mol Life Sci. 2017; 74(12): 2263–2282.
  4. Fu Yi, Kong W. Cartilage oligomeric matrix protein: matricellular and matricrine signaling in cardiovascular homeostasis and disease. Curr Vasc Pharmacol. 2017; 15(3): 186–196.
  5. de Gaetano M, Dempsey E, Marcone S, et al. Conjugated linoleic acid targets β2 integrin expression to suppress monocyte adhesion. J Immunol. 2013; 191(8): 4326–4336.
  6. Henein MY, Vancheri S, Longo G, et al. The role of inflammation in cardiovascular disease. Int J Mol Sci. 2022; 23(21).
  7. Jing R, Zhong QQ, Long TY, et al. Downregulated miRNA-26a-5p induces the apoptosis of endothelial cells in coronary heart disease by inhibiting PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2019; 23(11): 4940–4947.
  8. Kamranvar SA, Rani B, Johansson S. Cell cycle regulation by integrin-mediated adhesion. Cells. 2022; 11(16).
  9. Khatana C, Saini NK, Chakrabarti S, et al. Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis. Oxid Med Cell Longev. 2020; 2020: 5245308.
  10. Li DL, Kronenberg MW. Myocardial perfusion and viability imaging in coronary artery disease: clinical value in diagnosis, prognosis, and therapeutic guidance. Am J Med. 2021; 134(8): 968–975.
  11. Li P, Lv H, Zhang B, et al. Growth differentiation factor 15 protects SH-SY5Y cells from rotenone-induced toxicity by suppressing mitochondrial apoptosis. Front Aging Neurosci. 2022; 14: 869558.
  12. Malakar AKr, Choudhury D, Halder B, et al. A review on coronary artery disease, its risk factors, and therapeutics. J Cell Physiol. 2019; 234(10): 16812–16823.
  13. Mazat JP, Devin A, Ransac S. Modelling mitochondrial ROS production by the respiratory chain. Cell Mol Life Sci. 2020; 77(3): 455–465.
  14. Spadaccio C, Nenna A, Rose D, et al. The role of angiogenesis and arteriogenesis in myocardial infarction and coronary revascularization. J Cardiovasc Transl Res. 2022; 15(5): 1024–1048.
  15. Tsai TY, Leong IL, Cheng KS, et al. Lysophosphatidylcholine-induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells. Fundam Clin Pharmacol. 2019; 33(1): 52–62.
  16. Viola M, Karousou E, D'Angelo ML, et al. Extracellular matrix in atherosclerosis: hyaluronan and proteoglycans insights. Curr Med Chem. 2016; 23(26): 2958–2971.
  17. Waheed N, Elias-Smale S, Malas W, et al. Sex differences in non-obstructive coronary artery disease. Cardiovasc Res. 2020; 116(4): 829–840.
  18. Wang JF, Chen YY, Zhang SW, et al. ITGA5 promotes tumor progression through the activation of the FAK/AKT signaling pathway in human gastric cancer. Oxid Med Cell Longev. 2022; 2022: 8611306.
  19. Wang Y, Yang X, Jiang An, et al. Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J. 2019; 33(12): 13145–13160.
  20. Whayne TF. Low-density lipoprotein cholesterol (LDL-C): how low? Curr Vasc Pharmacol. 2017; 15(4): 374–379.
  21. Yao X, Jiang H, Li YH, et al. Kaempferol alleviates the reduction of developmental competence during aging of porcine oocytes. Anim Sci J. 2019; 90(11): 1417–1425.
  22. Yu F, Zhang Ya, Wang Z, et al. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics. 2021; 11(11): 5404–5417.
  23. Yu S, Zhang L, Liu C, et al. PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca elevation. Exp Cell Res. 2019; 379(2): 191–202.
  24. Zhang Y, Zhao J, Ren C, et al. Free fatty acids induce coronary microvascular dysfunction via inhibition of the AMPK/KLF2/eNOS signaling pathway. Int J Mol Med. 2023; 51(4).
  25. Zhao Xi, Sun Di, Xu RX, et al. Low-density lipoprotein-associated variables and the severity of coronary artery disease: an untreated Chinese cohort study. Biomarkers. 2018; 23(7): 647–653.