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

ABSTRACT Hyperuricemia is a common comorbidity of hypertension and probably has a causal relationship with hypertension. Alpha‐mangostin (α‐MG) has been reported to have uric acid lowering effect. This study aimed to investigate the dual effects of α‐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 α‐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 α‐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, α‐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 α‐MG may not be necessarily dependent on its urate‐lowering properties. α‐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 α‐MG as a novel anti‐hypertensive drug especially in patients with hyperuricemia. α‐Mangostin (α‐MG) effectively reduced blood pressure, promoted endothelial relaxation, and reversed vascular remodeling in Angiotensin II‐induced hypertensive mice. The mechanism involved balancing the ACE/Ang II/AT1R and ACE2/Ang (1‐7)/MasR axes, along with the upregulation of eNOS. Furthermore, α‐MG enhanced uric acid clearance through downregulation GLUT9, suggesting its potential as a novel antihypertensive agent, especially for patients with hyperuricemia.