Abstract 18942: Inhibition of β-arrestin 1 Prevents post-MI Maladaptive Ventricular Remodeling

Abstract

Remote (non-infarct) territory fibrosis is a significant cause of post-myocardial infarction (MI) heart failure (HF). We have previously shown that increased activity of β-arrestin 1 in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis. This study investigates the potential therapeutic role of β-arrestin 1 inhibition on CF biology in vivo. Adult male rats underwent LAD ligation to induce post-MI HF. β-arrestin 1 was inhibited by intra-coronary adenoviral-mediated delivery of a β-arrestin 1 inhibitor (Ad-Barr1ct) immediately following LAD ligation (n=11). Ad-Barr1ct contains a rat β-arrestin 1 C-terminal fragment (aa. 369-418). Control rats received a null adenovirus (n=10). Animals were studied prior to and up to 8 weeks (wks) post-MI and adenoviral delivery. There was a significant decline in LV function at 8 wks post-MI in Ad-null rats vs. pre-MI. Remote territory (non-infarct area) fibrosis increased by 8 wks post-MI consistent with adverse remodeling. Intra-coronary delivery of Ad-Barr1ct following LAD ligation significantly inhibited post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening and ejection fraction. Ad-Barr1ct also decreased peri-infarct and remote territory fibrosis. Consistent with these findings, Ad-arr1ct resulted in decreased α-SMA, collagen I, collegen III and fibronectin expression in CF isolated 8 wks post-MI vs. Ad-Null providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-Barr1ct. Targeted inhibition of β-arrestin 1 in the heart may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling post-MI.