Vanillic Acid Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension by Enhancing NO Signaling Pathways

Pulmonary arterial hypertension (PAH) is a severe progressive disease characterized by elevated mean pulmonary arterial pressure, right ventricular hypertrophy, and eventual progression to right heart failure and death. This study aimed to examine the effect of the natural product vanillic acid (VA) on monocrotaline (MCT)-induced PAH in rats. The arginase inhibitory activity and enzyme kinetic reaction of VA were also investigated. The results showed that VA could improve pulmonary arterial pressure, pulmonary artery vascular remodeling, and right ventricular remodeling induced by MCT in rats and reduce the degree of pulmonary tissue fibrosis. Moreover, VA downregulated the gene and protein expression levels of Hif-2 alpha, Hif-1 beta, and Arg2 and increased the P-eNOS/eNOS levels, thus increasing nitric oxide (NO) levels in PAH rats. Furthermore, VA was determined to be a mixed competitive arginase inhibitor with an IC50 of 26.1 mu M. In conclusion, the arginase inhibitor VA exerted protective effects on MCT-induced PAH and pulmonary vascular remodeling by enhancing NO signaling pathways.