TDB protects vascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced injury by targeting miR-34a to increase Bcl-2 expression

Abstract

Prolonged ischemia can result in apoptotic death of vascular endothelial cells and lead to ischemic vascular diseases including vascular dementia, arteriosclerosis and brain oedema. Finding protective strategies to prevent this is therefore an urgent mission. Recent studies have shown that dysregulation of microRNAs (miRNAs) can lead to imbalance of Bcl-2 family proteins and mitochondrial dysfunction, leading to further damage of vascular cells under ischemic conditions. However, whether miRNAs can be used as a drug target for treating vascular diseases is not fully understood. In this study, we observed that the natural product 2,4,5-trihydroxybenzaldehyde (TDB) could effectively inhibit vascular cell apoptosis following oxygen-glucose deprivation/reperfusion (OGD/R) by maintaining mitochondrial membrane potential (MMP) and suppressing activation of the mitochondria-dependent caspase-9/3 apoptosis pathway. Furthermore, we identified miR-34a, a crucial negative regulator of Bcl-2, as a target for the protective effect of TDB on vascular cells. TDB-induced suppression of miR-34a resulted in a significant upregulation of Bcl-2 protein, MMP maintenance, and the survival of vascular cells following OGD/R. Our findings suggest that targeting miR-34a with the natural product TDB may provide a novel strategy for the treatment of ischemic vascular injuries, and demonstrate the therapeutic potential in targeting miRNAs using appropriate small molecules.

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

“…caspase-9 cleaves and activates procaspase-3, a downstream executioner caspase protein, which cleaves various 'death substrates' and thereby triggers the apoptotic cell phenotype. A previous study demonstrated that the knockdown of miR-34a altered the integrity of the mitochondrial outer membrane and increased the release of cyto c from mitochondria, finally activating the caspase-mediated apoptotic pathway in vascular Ecs (20). In the present study, the results showed that the knockdown of miR-34a inhibited cleaved-caspase-3, -8, -9, Bax and cleaved-PARP, and increased Bcl-2 in the ox-LdL-treated HUVEcs.…”

“…Zhang et al (25) demonstrated that the inhibition of miR-155 improved high glucose-induced Ec injury by suppressing the activation of nuclear factor-κB. miR-34a is upregulated in atherosclerotic samples and is involved in the progression of atherosclerosis (21), in addition to possessing pro-apoptotic effects on Ecs (20). Previous miRNA microarray analysis confirmed that the levels of miR-34a are increased in the serum of patients with atherosclerosis.…”

“…miR-26a protects Ecs from ox-LdL-induced apoptosis in the setting of atherosclerosis by targeting transient receptor potential cation channel subfamily c member 6 (38). The natural product 2,4,5-trihydroxybenzaldehyde has been found to effectively inhibit oxygen-glucose deprivation/reperfusion-induced Ec injury via suppressing miR-34a (20). Therefore, it was hypothesized that miR-34a may modulate ox-LDL-mediated apoptosis in HUVECs.…”

“…However, whether miRNAs are also involved in ox-LdLinduced Ec apoptosis remains to be fully elucidated. Several studies have shown that miR-34a has pro-apoptotic effects on various cells, including vascular Ecs (19,20). A previous study revealed that miR-34a was upregulated in atherosclerotic samples (21).…”

<p>Ultrasound-Mediated Co-Delivery of miR-34a and sPD-1 Complexed with Microbubbles for Synergistic Cancer Therapy</p>

“…Bcl-2 related X (Bax) is a homologous to Bcl-2 and an apoptosispromoting gene in the Bcl-2 gene family. [40][41][42] Overexpression of Bax can antagonize the protective effect of Bcl-2 and lead to cell death. Our results shown that Bcl-2 were down expression in miR-34a/CLMBs group and miR-34a/CLMBs and sPD-1/CLMBs mixed group.…”