Cardiac‐specific overexpression of miR‐122 induces mitochondria‐dependent cardiomyocyte apoptosis and promotes heart failure by inhibiting Hand2

Abstract

Heart failure is characterized by the functional loss of ventricular contractility. It occurs following hypertrophy and ventricle deterioration resulting from cardiomyocyte apoptosis. 1 An early component of cardiomyocyte apoptosis in heart failure is the dysregulation of mitochondrial fission and fusion. [2][3][4][5][6][7] The relative rates of fusion and fission are normally tightly controlled, but during apoptosis, there is a dysregulation of key regulatory proteins like MFF, MFN1, MFN2, OPA1 and Drp1. 8 Much work has focused on characterizing the regulatory pathways governing mitochondrial fission and fusion in terms of how they become dysregulated in heart failure and in terms of identifying molecular targets for potentially blocking this dysregulation.MicroRNAs have gained significant attention as modulators of mitochondrial fission and fusion. MicroRNAs are endogenous, single-stranded, short RNA sequences (~22 nucleotides) that regulate target gene expression by binding to the 3' untranslated regions (UTRs) of target mRNAs. 9 The microRNAs miRNA-499, miRNA-140 and miRNA-30c have been shown to modulate mitochondrial fission

KLHL38 facilitates staurosporine‐induced apoptosis in HL‐1 cells via myocardin degradation

“…31 Abnormal activation of the mir-122/ Hand2/Drp1 signaling pathway leads to cardiomyocyte apoptosis, resulting in HF. 32 Here, we found that KLHL38 was highly expressed in cardiac tissue of HF patients and mouse model. And in STS-induced cardiomyocyte apoptosis model, it is further confirmed that KLHL38 could promote cardiomyocyte apoptosis, but STS induced apoptosis of cardiomyocytes was significantly inhibited after silencing KLHL38.…”

“…LncRNA KCNQ1OT1 facilitates cardiomyocyte apoptosis by targeting fused in sarcoma (FUS) in doxorubicin‐induced HF 31 . Abnormal activation of the mir‐122/Hand2/Drp1 signaling pathway leads to cardiomyocyte apoptosis, resulting in HF 32 . Here, we found that KLHL38 was highly expressed in cardiac tissue of HF patients and mouse model.…”

MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure

“…Furthermore, miR-122 interacts directly with a transcription factor regulating its own expression, and the effect of miR-122 on DRP1 is mediated by HAND2 (116). These findings demonstrate that miR-122 exerts a regulatory role in cardiomyocyte apoptosis via suppressing HAND2, which results in increased expression of DRP1, and ultimately leads to apoptosis (116).…”

“…MiR-122 is one of several miRNAs elevated in patients with HF, and plays a pivotal role in cardiac insufficiency by inducing cardiomyocyte apoptosis (115). Shi et al (116) found that DRP1 levels were increased in response to upregulation of miR-122, indicating that apoptosis (and cardiac dysfunction) increase through DRP1-mediated up-regulation of mitochondrial fission. Furthermore, miR-122 interacts directly with a transcription factor regulating its own expression, and the effect of miR-122 on DRP1 is mediated by HAND2 (116).…”

“…Shi et al (116) found that DRP1 levels were increased in response to upregulation of miR-122, indicating that apoptosis (and cardiac dysfunction) increase through DRP1-mediated up-regulation of mitochondrial fission. Furthermore, miR-122 interacts directly with a transcription factor regulating its own expression, and the effect of miR-122 on DRP1 is mediated by HAND2 (116). These findings demonstrate that miR-122 exerts a regulatory role in cardiomyocyte apoptosis via suppressing HAND2, which results in increased expression of DRP1, and ultimately leads to apoptosis (116).…”