Moldavoside ameliorates hypertension and autoantibodies targeting the angiotensin II type 1 receptor-induced endothelial damage via regulation of RhoE/CAV-1/eNOS axis

Globally, more than 100 million patients with resistant hypertension experience severe endothelial damage. Therefore, exploring the mechanisms underlying endothelial damage and developing effective interventions is urgently required. The clinical data and biochemical indicators of patients with resistant hypertension and those in the control group were collected. Correlation and regression analyses revealed that autoantibodies targeting the angiotensin II type 1 receptor (AT1-AA) were associated with endothelial damage and may serve as an important contributing factor. After isolation, extraction and purification of AT1-AA, tandem mass tag proteomics identified potential associations between AT1-AA and RhoE/CAV-1/STATs axis. In vitro experiments showed that AT1-AA induced endothelial damage by dephosphorylating eNOS at Ser1177 and suppressing RhoE expression. Network pharmacology analysis predicted that moldavoside may target multiple molecules including CAV-1, RhoE, STATs, and eNOS. Further investigation revealed that moldavoside protected HUVECs from AT1-AA-induced endothelial damage, RhoE downregulation and eNOS dephosphorylation; however, this protective effect was inhibited by an eNOS inhibitor. In vivo, endothelial damage and vascular remodeling induced by AT1-AA were reversed by moldavoside; however, endothelial-specific knockout of RhoE abolished the protective effect of moldavoside. Co-Immunoprecipitation, immunofluorescence colocalization, molecular dynamics simulation and immunoblotting revealed that CAV-1 facilitates the dephosphorylation of eNOS, which is counteracted by RhoE. Interestingly, AT1-AA induces the dephosphorylation of STAT3 at Tyr705, therefore inhibiting RhoE expression, a process that can be reversed by moldavoside. Moldavoside counteracts the dephosphorylation of STAT3 induced by AT1-AA, restoring the expression of RhoE. The restored RhoE promotes eNOS phosphorylation, which may contribute to the protection against AT1-AA-induced endothelial damage. 1. Serum autoantibodies targeting the angiotensin II type 1 receptor (AT1-AA) are positive in patients with resistant hypertension and are associated with hypertension and endothelial damage, representing a promising therapeutic target for hypertension. 2. AT1-AA suppresses the expression of RhoE by inhibiting the phosphorylation of STAT3 at Tyr705, leading to the dephosphorylation of eNOS at Ser1177, which induces endothelial damage. 3. Moldavoside demonstrates therapeutic potential through antagonism of AT1-AA-mediated pathophysiological effects.