Abstract 17416: miR-1468-3p Regulates Development of Cardiac Fibrosis

• DOI: 10.1161/circ.138.suppl_1.17416
• Publication Date: 2021-07-02T20:19:45Z
• Authors: Ruizhu Lin; Lea Rahtu-Korpela; Johanna Magga; Lasse Pakanen; Katja Porvari; Juhani Junttila; Heikki Huikuri; Risto Kerkelä
• Keywords: 03 medical and health sciences; 0302 clinical medicine

Background: Accumulation of extracellular matrix disturbs the electrical conduction and stiffens myocardium, leading to higher risk for arrhythmias and diastolic dysfunction. MicroRNAs (miRNAs) function in post-translational gene regulation, and aberrant alteration of miRNAs level has been implicated in cardiac pathologies.

Methods and Results: RNA sequencing of RNA samples of sudden cardiac death (SCD) victims with idiopathic myocardial fibrosis (IMF) for differentially expressed miRNAs identified miR-1468-3p. qPCR analysis validated that expression of miR-1468-3p is upregulated in hearts of SCD victims with IMF comparing to control subjects. However, the role and molecular function of miR-1468-3p in cardiac fibrosis are not known. We utilized human cardiac fibroblasts (hCFs) and gain- and loss-of-function approaches to study the role of miR-1468-3p in modulating fibroblast function. Overexpressing miR-1468-3p in hCFs resulted in an increase in expression of several fibrotic genes compared with hCFs transfected with control mir-mimic. Western blot analysis showed that miR-1468-3p mimic was sufficient to drive expression of collagen I and CTGF protein expression. Treatment of hCFs with miR-1468-3p antagomir did not alter expression of fibrosis-related gene at basal level, whereas miR-1468-3p inhibition significantly attenuated TGF-β1-induced collagen I and collagen III expression. Treatment of hCFs with miR-1468-3p antagomir blunted TGF-β1-induced collagen I and CTGF protein expression, but not TGF-β1-induced αSMA expression. Employing Sirius Red/Fast Green assay, we validated that depletion of miR-1468-3p antagonized both TGF-β1-triggered collagen and non-collagen protein production. Finally, we found that miR-1468-3p antagomir downregulated TGF-β1-induced collagen expression partially through the interference of TGF-β1/MAPK signals (p38 and JNK) and Integrin signaling.

Conclusions: Our data indicate a pro-fibrotic role of miR-1468-3p in modulating cardiac fibrosis, and manipulating the expression of miR-1468-3p may provide a therapeutic strategy for treatment of cardiac fibrosis.