Downregulation of microRNA‑34a inhibits oxidized low‑density lipoprotein‑induced apoptosis and oxidative stress in human umbilical vein endothelial cells

Abstract

Oxidized low‑density lipoprotein (ox‑LDL) promotes endothelial cell dysfunction, which is a primary risk factor for the development of atherosclerosis. A previous study reported that microRNA (miRNA/miR)‑34a is upregulated in atherosclerotic samples. However, its function and underlying mechanisms remain to be fully elucidated. In the present study, miRNA microarray analysis was performed to investigate the miRNA expression profile in atherosclerotic plaque tissues and examine the role of miR‑34a in ox‑LDL‑induced apoptosis of human umbilical vein endothelial cells (HUVECs). Cell viability, apoptosis and protein expression was determined by a cell counting kit‑8 assay, flow cytometry and western blot analysis, respectively. It was observed that miR‑34a was upregulated in atherosclerotic plaque tissues and that ox‑LDL treatment significantly increased the levels of miR‑34a in a dose‑dependent manner in the HUVECs. The knockdown of miR‑34a increased the protein expression of B‑cell lymphoma 2 (Bcl‑2) and cell viability, improved mitochondrial membrane potential, and decreased the activity of caspase‑3, number of apoptotic cells and release of cytochrome c from mitochondria in the ox‑LDL‑treated HUVECs. The results also demonstrated that the knockdown of miR‑34a suppressed the levels of ox‑LDL‑induced reactive oxygen species (ROS) in HUVECs. Additionally, it was found that Bcl‑2 was a target of miR‑34a in HUVECs, and that silencing Bcl‑2 abrogated the protective effects of the downregulation of miR‑34a on ox‑LDL‑induced apoptosis. These data indicated that the knockdown of miR‑34a protected against ox‑LDL apoptosis and ROS in HUVECs via inhibiting the mitochondrial apoptotic pathway, suggesting it may offer potential as a biomarker in the clinical diagnosis and as a target for the treatment of atherosclerosis.

Metformin promotes proliferation and suppresses apoptosis in Ox-LDL stimulated macrophages by regulating the miR-34a/Bcl2 axis

“…26 Moreover, downregulation of miR-34a suppressed Ox-LDL-induced apoptosis and oxidative stress in human umbilical vein endothelial cells. 27 However, the role of miR-34a in Ox-LDL stimulated macrophages is still unclear. Hence, we further explored whether metformin promoted proliferation and suppressed apoptosis in Ox-LDL stimulated macrophages through regulating miR-34a expression.…”

“…Previous studies reported that metformin could down-regulate miR-34a expression in high glucose condition and downregulation of miR-34a could suppress Ox-LDL-induced apoptosis. 26,27 Hence, we presumed that metformin may promote proliferation and suppressed apoptosis in Ox-LDL stimulated macrophages through regulating miR-34a expression. To conrm whether the pro-proliferation and antiapoptosis effect of metformin was mediated by miR-34a, we rst detected miR-34a expression in macrophages with Ox-LDL and metformin treatment.…”

“…18 Previous studies revealed that miR-34a was upregulated in atherosclerotic samples and could contribute to AS progression. [19][20][21] Nevertheless, how miR-34a was regulated and its functional role in Ox-LDL stimulated macrophages are still unclear. Previous studies reported that metformin could inhibit miR-34a expression in nonalcoholic fatty liver disease and in rat mesangial cells treated with high glucose.…”

Role of microRNAs in the Development of Cardiovascular Disease in Systemic Autoimmune Disorders

“…There is growing evidence that miRNAs control these pathologic processes including endothelial dysfunction (miR let-7g, mir-17-3p, miR-31, miR-146a, miR-155, miR-181 family, miR-221/-222,) [170][171][172][173][174][175], oxidative stress (miR-let-7a/b, miR-19b, miR-20a, miR-98, miR-126, miR-142-3p, miR-199a-3p and -5p, miR-200c, miR-221, miR-222, miR-328) [176][177][178][179][180][181][182][183][184][185][186][187][188][189], monocyte recruitment, differentiation and activation (miR-21, miR-23a-5p, miR-27a/b, miR-33, miR-34, miR-146a, miR-155, miR-212, miR-451, miR-590, miR-758-5p, [190][191][192][193][194][195][196][197][198][199][200][201] and inflammation/secretion of inflammatory cytokines (miR let-7g, miR-17-3p, miR-31, miR-146a, miR-155, miR-181a-3p/-5p, miR-181b, miR-221 and miR-222) [171,202,203]. Interestingly, a number of them are simultaneously involved in all those processes, suggesting common and/or cooperative activities, and underlying their relevance in the physiopathology of CVD.…”

MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

“…Both miR-98 and let-7a/b inhibit LOX-1 expression, which prevents oxLDL uptake into the endothelium [64,65]. Conversely, miR-34 antagonises oxLDL cell injury by targeting the cell-survival gene bcl-2 [66].…”