VSMC-Specific Deletion of FAM3A Attenuated Ang II-Promoted Hypertension and Cardiovascular Hypertrophy

Abstract

Rationale: Dysregulated purinergic signaling transduction plays important roles in the pathogenesis of cardiovascular diseases. However, the role and mechanism of vascular smooth muscle cell (VSMC)-released ATP in the regulation of blood pressure, and the pathogenesis of hypertension remain unknown. FAM3A (family with sequence similarity 3 member A) is a new mitochondrial protein that enhances ATP production and release. High expression of FAM3A in VSMC suggests it may play a role in regulating vascular constriction and blood pressure. Objective: To determine the role and mechanism of FAM3A-ATP signaling pathway in VSMCs in the regulation of blood pressure and the pathogenesis of hypertension. Methods and Results: In the media layer of hypertensive rat and mouse arteries, and the internal mammary artery of hypertensive patients, FAM3A expression was increased. VSMC-specific deletion of FAM3A reduced vessel contractility and blood pressure levels in mice. Moreover, deletion of FAM3A in VSMC attenuated Ang II (angiotensin II)-induced vascular constriction and remodeling, hypertension, and cardiac hypertrophy in mice. In cultured VSMCs, Ang II activated HSF1 (heat shock factor 1) to stimulate FAM3A expression, activating ATP-P2 receptor pathway to promote the change of VSMCs from contractile phenotype to proliferative phenotype. In the VSMC layer of spontaneously hypertensive rat arteries, Ang II-induced hypertensive mouse arteries and the internal mammary artery of hypertensive patients, HSF1 expression was increased. Treatment with HSF1 inhibitor reduced artery contractility and ameliorated hypertension of spontaneously hypertensive rats. Conclusions: FAM3A is an important regulator of vascular constriction and blood pressure. Overactivation of HSF1-FAM3A-ATP signaling cascade in VSMCs plays important roles in Ang II-induced hypertension and cardiovascular diseases. Inhibitors of HSF1 could be potentially used to treat hypertension.