Abstract 14843: Human Alpha1a-Adrenergic Receptor Genetic Variant Triggers Hypertension Associated Signaling Pathway
Stress-induced hypertrophy, characterized by changes in the structure of myocardium and blood vessels, is mediated by a variety of extracellular stimuli including G protein-coupled receptor (GPCR) agonists, growth factors and cytokines. Transactivation of epidermal growth factor receptor (EGFR) by GPCRs, for example by adrenergic receptors (AR), is one potential mechanism of hypertrophy in the heart. Three subtypes of α1ARs (α1a, α1b, α1d) are expressed in most sympathetic tissues and couple to the Gq/11 family of G proteins. Various cardiovascular disorders are associated with polymorphisms in genes regulating adrenergic signaling. Our current studies focus on molecular mechanisms and signaling pathways triggered by a naturally occurring human G247R SNP in the 3rd intracellular loop of α1aAR (247R) in cardiomyoblasts, vascular smooth muscle cells (SMC) and fibroblasts. We determined that constitutive expression of this SNP, originally identified in hypertensive patient, resulted in a β-arrestin1 dependent ~2-fold increased proliferation in Rat-1 fibroblasts compared with α1aAR-WT (WT) or α1b/α1dAR, that is serum and agonist-independent and is due to upregulation of MMP7 and ADAM12, EGFR transactivation, and ERK activation. Here we find that H9C2 rat cardiomyoblasts stably expressing 247R (100-400fmol/mg) change their morphology from myoblasts to fibroblast-like cells, while WT or non-transfected H9C2 cells do not, and exhibit ~7-fold increased proliferation compared to H9C2 or WT as determined by cell counts and thymidine incorporation assays; levels of pERK are also upregulated in 247R cells. Agonist stimulation of 247R, but not WT cells, results in hypertrophy of H9C2 cells as determined by leucine incorporation. Preliminary results suggest increased MMP2 mRNA levels in 247R cells consistent with similar observations in failing hearts. 247R expression in SMCs also induced increased proliferation compared with WT cells. Taken together, these data suggest that the naturally occurring human α1aAR genetic variant triggers β-arrestin/ MMP/ADAM dependent EGFR transactivation-mediated hyperproliferation and hypertrophy in different cardiovascular cell types and is a novel hypertension-associated signaling mechanism.
- © 2011 by American Heart Association, Inc.