Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling

Abstract

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular (LV) remodeling and clinical outcome in heart failure (HF) patients, though precise mechanisms remain obscure. Objective: To investigate the mechanism of miR-30d-mediated cardioprotection in HF. Methods and Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid (LNA)-based knock-down of miR-30d expression potentiates pathological LV remodeling, with increased dysfunction, fibrosis, and CM death. RNA-seq of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in CMs, induced by hypoxic stress and is acutely protective, targeting mitogen-associate protein kinase (MAP4K4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by CMs and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma EVs is associated with adverse remodeling in rodent models and human subjects, and is linked to whole blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of EV-contained miRNAs to trans regulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

Expression Profile of Circulating MicroRNAs in Dogs With Cardiac Hypertrophy: A Pilot Study

“…The miR-425 has been reported to have anti-fibrotic effect on heart by inhibiting TGFβ1 (44). The expression of miR-30d, which is selectively enriched in cardiomyocytes, is induced by hypoxic stress and inhibits MAP4K4 to reduce cardiac apoptosis (45). The miR-151 targets PLM and is known to prevent ischemia-induced arrhythmias (46).…”

MicroRNA-30 regulates left ventricular hypertrophy in chronic kidney disease

“…Correspondingly, cardiomyocyte-specific overexpression of calcineurin leads to an increase in collagen gene expression in the myocardium ( 62 ). Most recently, Li et al ( 63 ) demonstrated that miR-30d in cardiomyocytes may regulate fibroblasts’ activation via targeting integrin α 5 , and cardiomyocytes can release miR-30d–containing extracellular vesicles to inhibit fibroblast proliferation and activation, thus suppressing myocardium fibrosis in ischemic heart failure. Hence, miR-30 downregulation in cardiomyocytes may indirectly and directly activate fibroblasts and promote cardiac fibrosis.…”

Adding a “Notch” to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach

“…Patients with HF show lower levels of circulating miR-30d correlated with an adverse clinical outcome ( Melman et al, 2015 ; Xiao et al, 2017 ). In the rat and mouse models of ischemic HF, overexpression of miR-30d protects against cardiomyocyte apoptosis, myocardial fibrosis and improves cardiac remodeling, while miR-30d silencing causes opposite effects ( Li et al, 2021 ). Of interest, in pulmonary fibrosis miR-30d overexpression induces the activation of Notch signaling by regulating Jagged1 ( Zhao et al, 2018 ).…”