Targeting response gene to complement 32 to alleviate vascular remodeling

Summary/Abstract: Vascular remodeling is a fundamental pathological process occurring in artery wall during the development of numerous vascular diseases including artery restenosis following angioplasty and bypass surgery, hypertension, organ transplantation, atherosclerosis, and pulmonary arterial hypertension (PAH). Emerging evidence indicates that endothelial-mesenchymal transition (EndoMT) plays a critical role in the initiation and progression of vascular remodeling. However, the molecular mechanisms underlying the EndoMT process remain largely unknown. Preliminary studies indicate that response gene to complement 32 (RGC-32) is a novel protein factor essential for the EndoMT of pulmonary artery endothelial cells (PAECs). RGC-32 is induced by transforming growth factor (TGF)-β1 and hypoxia treatment. Knockdown of RGC-32 blocks while overexpression of RGC-32 exacerbates transforming growth factor (TGF)-β1-induced EndoMT of human PAECs. In vivo, RGC-32 is induced predominantly in PAECs of human PAH patients and hypoxia-induced PAH mice. RGC-32 deficiency (Rgc32-/-) attenuates the hypoxia-induced PAH as evidenced by the reduction of right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricle hypertrophy in hypoxia-treated Rgc32-/- mice. Rgc32-/- also alleviates the EndoMT that is correlated with the blockade of PAH, as shown by the restoration of endothelial marker VE-cadherin and CD31 and the suppression of mesenchymal cell marker N-cadherin and vimentin. These exciting data strongly support a novel hypothesis that RGC-32 promotes PAH development by facilitating EndoMT of PAECs. PAH is a rapidly progressive and currently incurable disease characterized by sustained increase in pulmonary vascular resistance, vascular remodeling, and right ventricular (RV) hypertrophy and failure. Pharmacotherapeutic efforts fail to reverse the disease development, and the prognosis of PAH remains poor with a 5-year survival rate of < 70%. Therefore, identifying novel therapeutic targets is clinically urgent. Preliminary studies suggest that RGC-32 is a potentially novel therapeutic target for PAH. Thus, a combination of pulmonary arterial endothelial cells and animal PAH models along with molecular, cellular, histological, and genetic approaches will be used to 1) determine the molecular mechanisms by which RGC-32 regulates EndoMT of PAECs, and 2) delineate the endothelial cell-specific roles of RGC-32 in PAH and EndoMT of PAECs in vivo. Successful completion of the proposed studies will advance our fundamental knowledge and understanding of the molecular mechanisms governing the development of PAH by establishing RGC-32 as a novel regulator for EndoMT of PAECs and PAH. The outcome of the project will also identify a highly promising drug target for future therapeutic intervention to combat PAH in clinic.