Novel Signaling Pathways Triggered By A Human Alpha1a-Adrenoceptor Genetic Variant

Alpha1‐adrenergic receptors (α1ARs) play an important role in cardiovascular disease. We reported that naturally occurring genetic variant of human α1aAR, with G247R SNP (247R) identified in hypertensive patient, leads to constitutive hyperproliferation of fibroblasts via βarrestin/MMP‐dependent EGFR‐transactivation. Here we examine if the 247R‐triggered hyperproliferation is generalizable in other cell types. Surprisingly, expression of 247R in cardiomyoblasts results in morphological and phenotypical changes to fibroblast‐like cells. RNA and protein expression levels of FSP1, DDR2, MMP2, vimentin, Troponin I, βMHC confirm fibroblast‐like phenotype and cells exhibit agonist‐induced hypertrophy and constitutive, serum‐independent 2–3‐fold increased proliferation. Interestingly, hypertrophy but not proliferation is inhibited by prazosin, an α1aAR‐inverse agonist, suggesting two independent pathways triggered by 247R: proliferation is caused by Gq‐independent, but βarrestin/Src‐dependent EGFR transactivation while hypertrophy is Gq‐dependent. In summary, our data suggest that the naturally occurring human α1aAR genetic variant triggers βarrestin/MMP/ADAM dependent EGFR transactivation pathway leading to hyperproliferation or hypertrophy in different cardiovascular cell types and is a novel hypertension‐associated signaling mechanism.