MicroRNA let-7-TGFBR3 signalling regulates cardiomyocyte apoptosis after infarction

Abstract

Background Myocardial infarction (MI) is a life-threatening disease, often leading to heart failure. Defining therapeutic targets at an early time point is important to prevent heart failure. Methods MicroRNA screening was performed at early time points after MI using paired samples isolated from the infarcted and remote myocardium of pigs. We also examined the microRNA expression in plasma of MI patients and pigs. For mechanistic studies, AAV9-mediated microRNA knockdown and overexpression were administrated in mice undergoing MI. Findings MicroRNAs let-7a and let-7f were significantly downregulated in the infarct area within 24 h post-MI in pigs. We also observed a reduction of let-7a and let-7f in plasma of MI patients and pigs. Inhibition of let-7 exacerbated cardiomyocyte apoptosis, induced a cardiac hypertrophic phenotype, and resulted in worsened left ventricular ejection fraction. In contrast, ectopic let-7 overexpression significantly reduced those phenotypes and improved heart function. We then identified TGFBR3 as a target of let-7, and found that induction of Tgfbr3 in cardiomyocytes caused apoptosis, likely through p38 MAPK activation. Finally, we showed that the plasma TGFBR3 level was elevated after MI in plasma of MI patients and pigs. Interpretation Together, we conclude that the let-7-Tgfbr3-p38 MAPK signalling plays an important role in cardiomyocyte apoptosis after MI. Furthermore, microRNA let-7 and Tgfbr3 may serve as therapeutic targets and biomarkers for myocardial damage. Fund Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Thematic Research Program and the Summit Research Program, Taiwan.

let-7 microRNAs: Their Role in Cerebral and Cardiovascular Diseases, Inflammation, Cancer, and Their Regulation

“…Cardiomyocyte apoptosis is considered a significant event during the development of cardiomyopathy. let-7 has been shown to target TGF-3β and regulate cardiomyocyte apoptosis after MI [149]. Bioinformatic predictions have shown several genes, such as TBX5, FOXP1, HAND1, AKT2, and PPARGC1A, which are related to cardiac development, to be targets of different let-7s (let-7a/7d/7e/7f ) [150].…”

microRNAs involved in psoriasis and cardiovascular diseases

“…let-7a downregulated the expression of its target Calmodulin (CaM) protein, that together with Ca 2+ induces the hypertrophic genes transcription (147). let-7a was found downregulated in myocardium of pigs after MI and also in plasma of humans and pigs after MI (148). In this study a let-7a overexpression was shown to be cardiac protective via inhibition of TGFBR3-p38 MAPK signalling pathways, that regulates cardiomyocyte apoptosis (148).…”

“…let-7a was found to be downregulated in the myocardium of pigs after MI and also in the plasma of humans and pigs after MI ( 148 ). In this study, a let-7a overexpression was shown to be cardiac protective via inhibition of TGFBR3-p38 MAPK signaling pathways that regulate cardiomyocyte apoptosis ( 148 ).…”

Identification of Two Long Non-Coding RNAs AC010082.1 and AC011443.1 as Biomarkers of Coronary Heart Disease Based on Logistic Stepwise Regression Prediction Model

“…Besides, these two DElncRNAs affected TGFBR3 expression by co-regulating the miR-27a-3p sponge via bioinformatics prediction. TGFBR3 expression is significantly upregulated in patients after myocardial infarction and may serve as a therapeutic target and biomarker for myocardial damage by activating p38 MAPK to induce cardiomyocyte apoptosis ( Chu et al, 2011 ; Chen et al, 2019 ). Moreover, it has been found that lncRNA SOX2-OT exacerbates hypoxia-induced cardiomyocyte injury by regulating the miR-27a-3p/TGFβR1 axis ( Yang and Lin, 2020 ).…”