α-Mangostin Attenuates Blood Pressure and Reverses Vascular Remodeling by Balancing ACE/AT1R and ACE2/Ang-(1-7)/MasR Axes in Ang II-Infused Hypertensive Mice

Hyperuricemia is a common comorbidity of hypertension and probably has a causal relationship with hypertension. Alpha-mangostin (alpha-MG) has been reported to have uric acid lowering effect. This study aimed to investigate the dual effects of alpha-MG on blood pressure (BP) and uric acid levels in angiotensin II (Ang II)-infused hypertensive mice. Male C57BL/6 mice were randomized into five groups: control, Ang II infusion (500 ng/kg/min for 2 weeks), Ang II infusion with gavage administration of alpha-MG 4.0 and 8.0 mg/kg and benzbromarone (25 mg/kg) respectively. BP, uric acid levels, vascular structure and function, and renin-Ang II system expressions in the aorta were assessed. Treatment with alpha-MG reduced BP, improved endothelial relaxation, and reversed aortic wall thickening and collagen deposition in Ang II-induced hypertensive mice. It also downregulated Ang II receptor 1 (AT1R) and angiotensin converting enzyme (ACE) expression, while upregulating ACE2, Mas receptor (MasR), and angiotensin (1-7) in the aorta. Moreover, alpha-MG demonstrated a significant enhancement in uric acid clearance and reduction in serum uric acid levels. Conversely, benzbromarone did not result in a decrease in BP, indicating that the hypotensive effect of alpha-MG may not be necessarily dependent on its urate-lowering properties. alpha-MG can attenuate Ang II-induced hypertension and reverse vascular remodeling, potentially by balancing the ACE/Ang II/AT1R axis and the ACE2/Ang-(1-7)/MasR axis. Our findings provide insights into alpha-MG as a novel anti-hypertensive drug especially in patients with hyperuricemia.