Abstract 5905: Osteogenic Transcription Factor Runx2 Suppresses Atrial and B-Type Natriuretic Peptide Gene Expression in Rat Cardiacmyocytes: Possible Role of Runx2 in Cardiac Fibrosis
Cardiac fibrosis is regulated by balance between pro- and anti-fibrotic peptides produced by cardiac myocytes. Recent study showed that myocardial expression of Runx2, runt domain containing transcription factor also known as Cbfa1 that is originally identified as a factor essential for bone formation, was significantly upregulated in patients with end-stage heart failure. However, little investigation has critically examined a role for Runx2 in the gene expression in cardiac myocytes. RT-PCR analysis of mRNA prepared from neonatal cardiac myocytes transduced with adenovirus expressing Runx2 (Ad-Runx2) showed that Runx2 downregulated expression of natriuretic peptide genes (ANP and BNP) while expression of connective tissue growth factor (CTGF) and TGF-beta, potent mediators of cardiac fibrosis, was not changed. Enzyme-linked immunosorbent assay showed that basal ANP and BNP secretion was markedly decreased in cardiomyocytes expressing Runx2. Furthermore, Runx2 significantly attenuated an induction of ANP and BNP secretion by endothelin-1 and angiotensin II. Luciferase assays showed that transcription driven by ANP and BNP promoters was markedly inhibited by cotransfected Runx2 expression vector. Of note, myocardin-mediated activation of ANP and BNP promoters was abolished by Runx2, suggesting that Runx2 interferes with the cardiac-specific transcription machinery. These results demonstrate that Runx2 negatively regulates ANP and BNP gene expression without affecting the CTGF and TGF-beta. Given that natriuretic peptides and profibrotic genes play a counterregulatory role in cardiac fibrosis, these findings allude to the notion that an induction of Runx2 in severe heart failure promotes cardiac fibrosis which further deteriorate cardiac function.