Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration

Abstract

The goal of replenishing the cardiomyocyte (CM) population using regenerative therapies following myocardial infarction (MI) is hampered by the limited regeneration capacity of adult CMs, partially due to their withdrawal from the cell cycle. Here, we show that microRNA-128 (miR-128) is upregulated in CMs during the postnatal switch from proliferation to terminal differentiation. In neonatal mice, cardiac-specific overexpression of miR-128 impairs CM proliferation and cardiac function, while miR-128 deletion extends proliferation of postnatal CMs by enhancing expression of the chromatin modifier SUZ12, which suppresses p27 (cyclin-dependent kinase inhibitor) expression and activates the positive cell cycle regulators Cyclin E and CDK2. Furthermore, deletion of miR-128 promotes cell cycle re-entry of adult CMs, thereby reducing the levels of fibrosis, and attenuating cardiac dysfunction in response to MI. These results suggest that miR-128 serves as a critical regulator of endogenous CM proliferation, and might be a novel therapeutic target for heart repair.

Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats

“…miRNAs are small endogenous non-coding RNAs composed of [19][20][21][22][23][24] nucleotides that bind to imperfect sequence sites of target mRNA and recruit the RNA-induced silencing complex, causing either degradation or inhibition of protein translation [11]. Generally, one gene can be repressed by multiple miRNAs, and one miRNA may repress multiple target genes, so miRNAs are recognized as important regulators involved in various cellular processes, including differentiation, proliferation, necrosis, and apoptosis [12][13][14]. Recent studies have revealed that multiple miRNAs engage in the regulation of cardiovascular formation, development, and function [14].…”

“…Generally, one gene can be repressed by multiple miRNAs, and one miRNA may repress multiple target genes, so miRNAs are recognized as important regulators involved in various cellular processes, including differentiation, proliferation, necrosis, and apoptosis [12][13][14]. Recent studies have revealed that multiple miRNAs engage in the regulation of cardiovascular formation, development, and function [14]. For example, miR-21 exerts anti-apoptotic function via targeting Fas ligand or programmed cell death 4 (PDCD4) [15][16][17].…”

Combining Nanomaterials and Developmental Pathways to Design New Treatments for Cardiac Regeneration: The Pulsing Heart of Advanced Therapies

“…Here we refer to heart-specific microRNAs known together as myomiRs (myo = muscle + miR = microRNA), such as mir-128, miR-19a/19b, and other miRNAs with known effects on the heart. They were recently found to play a role in pivotal cell functions involved in cardiac regeneration, i.e., proliferation, reprogramming and differentiation (Huang et al, 2018;Gao et al, 2019).…”

Reporting animal research: Explanation and Elaboration for the ARRIVE guidelines 2019

“…The correct insertion of the miR-128 cassette and successful removal of the neomycin cassette were confirmed by PCR analysis with the primers listed in Supplementary Table 1." [113] 2) "The C57BL/6J (Jackson) Los Angeles, CA). These mice were originally congenic C57BL/6J (backcrossed for five generations) and were then inbred (cousin matings) over 14 y, during which time they were outbred with C57BL/6JOlaHsd mice on three separate occasions."…”