Abstract 18134: Cardiomyocyte Overexpression of the alpha1A-Adrenergic Receptor in the Rat Protects Post-Infarct Heart Failure through Angiogenesis and the MEK-ERK Pathway

Abstract

α1A-Adrenergic receptors (α1A-AR) are important for regulating cardiac contractility, but whether they regulate coronary vessels is not known. To examine this we investigated the effects of chronic, complete coronary artery occlusion (CAO) in rats with cardiac myocyte-restricted transgenic (TG) α1A-AR overexpression, since protection of the heart with complete CAO requires increased blood flow. 4 weeks after permanent left anterior descending CAO TG rats displayed improved contractility vs. non-transgenic littermates (NTL) (n=8/group, p<0.05): 23% higher in LV dP/dt (7188±167mmHg/s), 13% higher in LV ejection fraction (57±0.9) and 23% lower in end-systolic wall stress (LVSWS) (79±6dynes/cm2) compared to NTLs. The scar size at 4 wks after CAO was significantly smaller in TG rats (18±2%) compared to NTL rats (28±3%), p<0.05, but more importantly there were increased blood vessels within the scar in the TG rat hearts suggesting angiogenesis. This was confirmed using colored microspheres to measure coronary blood flow, which was higher in area at risk in TGs (1.4±0.2ml/min/g) as compared to NTLs (0.5±0.08ml/min/g), p<0.05. This increased blood flow was further supported by a 41% increase in arterial density within the ischemic zone compared to NTLs at 2 weeks after CAO. In addition, capillary density was also found to be significantly increased, by 18% in the remote zone, compared to 2109 caps/mm2 in NTL. Utilizing an In vitro model, treatment with 25μM A61603 for 48 hours in cultured NTL neonatal myocytes resulted in an increase in VEGF-A secretion into the culture media and 26% increase in vascular tubule formation in HUVECs by a paracrine mechanism coinciding with an increased VEGF-A concentration compared to vehicle treated myocytes. Since VEGF is linked to the MEK-ERK signaling pathway, we blocked this mechanism by chronically administering the MEK blocker, U0126, sc. In these rats LV function was no longer different after 4 wks permanent CAO in TG and WTL treated with the blocker. Therefore, overexpression of cardiac myocyte specific α1A-AR in rats protected against cardiac dysfunction and remodeling associated with chronic myocardial infarction through the MEK-ERK pathway and via angiogenesis with a VEGF-A related paracrine mechanism.