The microRNA‐204‐5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction

Abstract

Background MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA‐204‐5p (miR‐204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood. Methods: We performed RNA‐sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR‐204 five weeks after trans‐aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR‐204. Results The stretch induces miR‐204 expression, and miR‐204 inhibits the stretch‐induced hypertrophic response of H9C2 cells. The mice lacking miR‐204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno‐associated virus serotype‐9‐mediated cardioselective miR‐204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR‐204 knockout mice following pressure overload suggested deregulation of apelin‐receptor (APJ) signalling. We found that the stretch‐induced extracellular signal‐regulated kinase 1/2 (ERK1/2) activation and hypertrophy‐related genes expression depend on the APJ, and both of these effects are subject to miR‐204 levels. The dynamin inhibitor dynasore inhibited both stretch‐induced APJ endocytosis and ERK1/2 activation. In contrast, the miR‐204‐induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR‐204 increases the expression of ras‐associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis. Conclusions Our results show that miR‐204 regulates trafficking of APJ and confers resistance to pressure overload‐induced CH/CD, and boosting miR‐204 can inhibit the development of CH/CD.

γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet

“… 33 miR-204 is highly expressed in vascular endothelial cells, 33 , 64 pancreatic β-cells, 97 , 98 and cardiomyocytes. 101 The inhibition or genetic deletion of miR-204 improves endothelial function and glycemic control despite obesity in the genetically diabetic db / db mice. 33 , 99 Castaño et al reported that the systemic administration of serum exosomes isolated from obese mice overexpressed miR-122 and promoted obesity and glucose intolerance in the lean mice by regulating PPAR-α in the epididymal white adipose tissue.…”

Dynamin-Independent Mechanisms of Endocytosis and Receptor Trafficking

“…However, their role in endocytosis and intracellular trafficking remains largely unknown. Over the past decade, research on miRNAs has shown their involvement in endocytosis processes [ 103 , 104 , 105 ]. For instance, the miR-199 family (miR-199a-5p and miR-199b-5p) markedly regulates the expression of endocytosis mediators such as clathrin heavy chain (CLTC), Rab5A, LDLR, and caveolin-1 [ 103 ].…”

“…However, it is unknown whether altered expression of these proteins by miRNAs affects their endocytosis and contributes to the observed phenotype. We recently reported that miR-204 promotes APJ (apelin-receptor) endocytosis via a dynamin-independent, calcium-dependent mechanism and confers protection against cardiac hypertrophy and dysfunction [ 104 ]. Others have also reported that miR-regulated calcium-mediated receptor endocytosis is involved in maintaining neuronal synaptic plasticity.…”

“…Loss of miR-103/107 causes dysregulation of micropinocytosis with the formation of large vacuoles, primarily through the upregulation of Src, Ras, and Ankfy1 [ 109 ]. miRNAs are not only involved in cellular function through proteins or GPCRs endocytosis but also determine signaling activation and outcome [ 103 , 104 , 105 , 107 ]. For example, miR-133α promotes the recycling of NTR1 and regulates neurotensin proinflammatory signaling [ 106 , 107 ].…”

“…For example, miR-133α promotes the recycling of NTR1 and regulates neurotensin proinflammatory signaling [ 106 , 107 ]. On the other hand, cardiac miR-204-5p favors dynamin-independent-calcium mediated APJ endocytosis over dynamin-dependent endocytosis and improves cardiac dysfunction [ 104 ]. Together, miRNA’s role in endocytosis regulation is emerging.…”