MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40

Abstract

An increasing body of evidence indicates that inflammation and apoptosis are involved in the development of acute myocardial infarction (AMI). In this study, we sought to investigate the specific role and the underlying regulatory mechanism of miR-145-5p in myocardial ischemic injury. H9c2 cardiac cells were exposed to hypoxia to establish a model of myocardial hypoxic/ischemic injury. We found that miR-145-5p was notably down-regulated, while CD40 expression was highly elevated in H9c2 cells following exposure to acute hypoxia. Additionally, hypoxia markedly enhanced the inflammatory response, as reflected by an increase in the secretion of the cytokines IL-1β, TNF-α, and IL-6, whereas the introduction of miR-145-5p effectively suppressed inflammatory factor production triggered by hypoxia. Furthermore, we observed hypoxia stimulation significantly augmented apoptosis accompanied by a decrease in the expression of Bcl-2 and an increase in the expression of Bax, Caspase-3, and Caspase-9. However, augmentation of miR-145-5p led to a dramatic prevention of hypoxia-induced apoptosis. Importantly, we identified CD40 as a direct target of miR-145-5p. Interestingly, the depletion of CD40 with small interfering RNAs (siRNAs) apparently repressed the production of inflammatory cytokines and apoptosis in the setting of acute hypoxic treated. Taken together, these data demonstrated that miR-145-5p may function as a cardiac-protective molecule in myocardial ischemic injury by ameliorating inflammation and apoptosis via negative regulation of CD40. The study gives evidence that miR-145-5p provides an interesting strategy for protecting cardiomyocytes from hypoxia-induced inflammatory response and apoptosis.

Expression of VEGFA‐regulating miRNAs and mortality in wet AMD

“…39 Decreased levels miR-145-5p levels enhance the secretion of IL-1β, TNF-α and IL-6 during hypoxia. 40 Therefore, miR-145-5p can be considered as a therapeutic target to suppress the inflammatory response and to prevent the apoptosis occurring in hypoxic conditions, a characteristic of wet AMD. 41,42 miR-205-5p was shown to regulate EMT through the PI3K/ AKT pathway.…”

MiRNA expression profiles in healthy OSAHS and OSAHS with arterial hypertension: potential diagnostic and early warning markers

“…Moreover, miR-145/Smad3 signaling pathway might promote OSAHS-induced aortic remodeling, which might be initiated by inflammation and oxidative stress [ 62 ]. In addition, hypoxia was found to aggravate inflammatory response and miR-145-5p might play an anti-inflammatory role to protect cells from ischemic and hypoxic injury [ 63 ]. It is well-known that, during sleep, intermittent hypoxia can cause sympathetic activation, evoke systemic inflammation, oxidative stresses and vascular dysfunction [ 64 – 66 ].…”

MicroRNA Expression Profile Changes after Cardiopulmonary Bypass and Ischemia/Reperfusion-Injury in a Porcine Model of Cardioplegic Arrest

“…This suggests that myocardial miR-122 might serve as a novel therapeutic target to reduce apoptosis and, subsequently, improve cardiac recovery in patients undergoing CABG. In addition, upregulation of miR-499-3p, miR-142-3p and miR-145-3p initiate cardioprotection via activation of anti-apoptotic and anti-inflammatory pathways in cardiomyocytes [25][26][27]. An important finding of our study is the upregulation of miR-142-3p in cardiac tissue in the on-pump group.…”