VSMC-Specific Deletion of FAM3A Attenuated AngII-Promoted Hypertension and Cardiovascular Hypertrophy.

Rationale: Dysregulated purinergic signaling transduction plays important roles in the pathogenesis of cardiovascular diseases. However, the role and mechanism of 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 AngII-induced vascular constriction and remodeling, hypertension, and cardiac hypertrophy in mice. In cultured VSMCs, AngII 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 SHR rat arteries, AngII-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 SHR 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 AngII-induced hypertension and cardiovascular diseases. Inhibitors of HSF1 could be potentially used to treat hypertension.