miR-124-3p and miR-181a-5p Mediate AT1-Receptor Autoantibody Induced Fetal Rat Cardiac Remodeling via Increased VCAN Expression

Abstract Autoantibodies against angiotensin II type 1 receptor (AT1-AA) are prevalent in preeclampsia. They induce fetal cardiac structural remodeling in late pregnancy via still unknown mechanisms, the subject of this study’s investigation. MicroRNA array revealed differential expression of microRNAs in fetal hearts exposed to AT1-AA. miR-124-3p and miR-181a-5p, the most significantly altered microRNAs, were significantly enriched in the myocardium. Gain- and loss-of-function experiments demonstrated that miR-124-3p and miR-181a-5p governed cardiomyocyte phenotype. Overexpression of miR-124-3p or inhibition of miR-181a-5p activated neonatal rat cardiomyocyte proliferation and size (the converse also being true). Moreover, miR-124-3p overexpression and miR-181a-5p inhibition acted in concert to exacerbate the effects of AT1-AA (increasing the size and proliferation of neonatal rat cardiomyocytes). Through TMT™ quantitative proteomics and luciferase reporter gene assay, miR-181a-5p and miR-124-3p respectively target the 3’ UTR and 5’UTR of VCAN, and oppositely regulate its expression. VCAN knockdown in neonatal rat cardiomyocytes blocked the pathological effect of AT1-AA. Furthermore, ELISA demonstrated positive correlation between AT1-AA expression and VCAN level in preeclamptic patient umbilical cord blood. Our study demonstrates that upregulation of miR-124-3p promotes VCAN expression, and miR-181a-5p downregulation decreases VCAN inhibition, thereby co-mediating AT1-AA induced fetal cardiac remodeling.