Differential regulation of the HIF-1α/apoptosis axis by miR-126-5p in cardiac cells during ischemia/reperfusion injury.

Abstract

Background: MicroRNAs (miRs) regulate gene expression post-transcriptionally and are transported by high-density lipoproteins (HDL). Hypercholesterolemic HDL particles are enriched with miR-126-3p/5p, which can be delivered to endothelial cells, leading to the downregulation of hypoxia-inducible-factor-1α (HIF-1α), a key transcription factor involved in metabolic responses to hypoxia and cell survival during myocardial ischemia/reperfusion (I/R).

Objective: To investigate the effects of miR-126 mimic and inhibitor transfection on the HIF-1α/apoptosis axis in cardiac cell constituents under experimental I/R.

Methods: Firstly, specific durations of I/R were established for cardiac cells (cardiomyocytes, fibroblasts, endothelial cells, and macrophages) based on their susceptibility to metabolic changes and cell death. Then, we assessed the impact of transfecting these cells with mimic-miR-126-5p and anti-miR-126-5p to the selected timings of I/R on the HIF-1α/apoptosis axis.

Results: Endothelial cells were resistant to I/R and fibroblasts were sensitive to ischemia whereas cardiomyocytes displayed high metabolic flexibility. Endogenous miR-126 expression was exclusively found in endothelial cells. Transfection with anti-miR-126 increased HIF-1α transcription in endothelial cells and cardiomyocytes, while reducing HIF-1α levels in fibroblasts, resulted in decreased transcript levels of apoptotic markers. HIF-1α transcript levels remained unchanged in macrophages and transfection with mimic-miR-126 exerted no changes in the HIF-1α/apoptosis axis in all tested cells.

Conclusions: miR-126 differentially regulates HIF-1α/apoptosis expression in cardiac cells exposed to experimental I/R and may serve as a potential therapeutic target for enhancing myocardial resilience in the setting of myocardial infarction.