Abstract 339: Runx1 Knock-down by Adeno Associated Viral Mediated-delivery of Short Hairpin RNA Preserves Cardiac Contractility Following Myocardial Infarction

Abstract

Myocardial infarction (MI) is a leading cause of heart failure (HF) and mortality worldwide. Preservation of contractile function and prevention of adverse cardiac remodelling following MI are essential to limit progression to HF. Expression of the Runx1 transcription factor in border zone cardiomyocytes is increased within 24 hours after MI. Genetically modified mice with Runx1 deficiency demonstrate an absence of cardiac dilation and preservation of left ventricular (LV) contractility following MI without a change of infarct size. Here, we investigate if adeno-associated viral (AAV)-mediated gene transfer to knock-down Runx1 expression post-MI attenuates adverse cardiac remodelling in mice. Male C57BL/6J mice underwent LAD ligation followed by intravenous injection of AAV-Runx1-shRNA or control AAV-scramble-shRNA (1x10 11 viral genomes). LV contractility (% fractional shortening, FS) was assessed by M-mode echocardiography. RNAscope assessed Runx1 expression in border zone cardiomyocytes and infarct size was histologically quantified using Picro sirius red stain. Runx1 expression within border zone cardiomyocytes was reduced by 30% in AAV-Runx1-shRNA treated mice (37.8±4.5 vs. 53.9±6.4% of cardiomyocytes; AAV-Runx1-shRNA vs. control). LV contractile function was significantly preserved as early as 1 day post-MI (%FS, day 1; 37.7±1.4 vs . 27.6±1.4, day 7; 37.2 ±1.2 vs .28.2±1.4; LV internal dimension during systole day 1; 2.9±0.2 vs . 2.4±0.1, day 7; 3.1±0.2 vs . 2.5±0.1mm; AAV-Runx1-shRNA vs. control, P <0.05). Interestingly, infarct size was reduced with AAV-Runx1-shRNA (31.7±2.0 vs . 40.4±1.4% of LV; AAV-Runx1-shRNA vs . control, P <0.05). In conclusion, a therapeutic approach utilising AAV-mediated knock-down of Runx1 preserved LV contractility and reduced infarct size following MI. These data further highlight Runx1 as a key driver of adverse cardiac remodelling and a therapeutic target with translational potential to prevent adverse cardiac remodelling following MI.