MiR-28 inhibits cardiomyocyte survival through suppressing PDK1/Akt/mTOR signaling

Abstract

MicroRNAs play critical roles in regulating cell survival under multiple pathological conditions of heart diseases. Oxidative stress-induced apoptosis contributes greatly to heart ischemia-reperfusion injury. Herein, we describe a novel regulatory role of miR-28 on the survival of cardiomyocytes. We show that miR-28 was upregulated in cardiomyocytes treated with hydrogen peroxide (HO). MiR-28 gain of function sensitized cell apoptosis, whereas miR-28 loss of function partially rescued cell apoptosis induced by HO. Importantly, we observed a significant reduction in Akt/mammalian target of rapamycin (mTOR) signaling activity after miR-28 treatment. Luciferase activity assay and western blot analysis both revealed that, phosphoinositide-dependent kinase-1 (PDK1), which is critical for Akt activation, was directly and negatively modulated by miR-28. Our results therefore indicate that miR-28 regulates oxidative stress-induced cell apoptosis in heart muscle cells, which possibly involves a PDK1/Akt/mTOR-dependent mechanism. MIR-28 could serve as a critical therapeutic target to diminish oxidative stress-induced cell death in the heart.

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“…As an essential integrator of growth factor inputs and nutrients, mTOR regulates cell growth in eukaryotes. It was specifically pointed out that miR‐28 inhibits cardiomyocyte survival by suppressing PDK1/Akt/mTOR signaling pathway, indicating its potential to serve as a critical therapeutic target to decrease oxidative stress‐induced cell death in the heart …”

The Encystment-Related MicroRNAs and Its Regulation Molecular Mechanism in Pseudourostyla cristata Revealed by High Throughput Small RNA Sequencing

“…As for miR-28, some studies showed that miR-28 was positively associated with cell death, overexpression of miR-28 played a detrimental role to cell survival, and the oxidative stress induced apoptosis was indeed rescued by an miR-28 antisense inhibitor [27]. In our study, it was revealed that the downregulation of miR-28 was beneficial for the cysts to survive in adversity.…”

Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases

“…Prevention of the loss of cardiomyocyte during I/R injury is the primary focal point and strategic approach to avoid cardiac dysfunction post-MI, which can potentially be achieved by regulating apoptosis and autophagy [ 189 ]. Experiments using primary neonatal cultured mouse cardiomyocytes identified a direct link between miR-28 and PDK1, an immediate upstream regulator of mTOR in the PI3K pathway [ 190 ]. Induction of oxidative stress in cardiomyocyte using hydrogen peroxide elevated the expression of miR-28 and increased apoptosis-mediated cell death [ 190 ].…”

“…Experiments using primary neonatal cultured mouse cardiomyocytes identified a direct link between miR-28 and PDK1, an immediate upstream regulator of mTOR in the PI3K pathway [ 190 ]. Induction of oxidative stress in cardiomyocyte using hydrogen peroxide elevated the expression of miR-28 and increased apoptosis-mediated cell death [ 190 ]. Interestingly, overexpression of miR-28 downregulated p-AKT, p-p70, and p-mTOR suggesting a direct interference of mTOR signaling by miR-28 [ 190 ].…”