Novel Mechanism for Sympathetically‐Mediated Hypertension by Naturally Occurring Human Alpha1aAR Genetic Variant

Abstract

α1a‐Adrenergic receptors (α1aARs) control human blood pressure by mediating vasoconstriction in small arterial resistance vessels; this has important implications in regulation of hypertension. A recent finding is that matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase (ADAMs) play key roles in development of hypertension by shedding growth factors and activating some signaling pathways. We previously identified a naturally occurring single nucleotide polymorphism (SNP) G247R in the third intracellular loop of α1aAR (α1aAR‐247R) in a patient with severe hypertension. Expression of this SNP in Rat‐1 fibroblasts results in unique, striking 2‐fold increased proliferation compared with wild type (α1aAR‐WT) or other α1AR subtypes, α1b/α1d. In this study we elucidate the molecular mechanisms and signaling pathways responsible for this unique proliferation triggered by α1aAR‐247R. We show for the first time that elevated levels of MMP‐7 and ADAM‐12 in cells expressing α1aAR‐247R are responsible for EGFR transactivation, ERK activation and increased cell proliferation; a pathway confirmed using EGFR, MMP and ERK specific inhibitors. Importantly, we show that accelerated proliferation triggered by α1aAR‐247R is serum and agonist independent. Thus, these new data suggest a novel mechanism of sympathetically‐mediated hypertension in humans with this naturally occurring SNP.