Resveratrol is an arginase inhibitor contributing to vascular smooth muscle cell vasoconstriction via increasing cytosolic calcium

Abstract

The contractility of vascular smooth muscle cells (VSMCs) controls the lumen diameter of vessels, thus serving a role in regulating blood pressure and organ blood flow. Although arginases are known to have numerous effects in the biological activities of VSMCs, the effects of arginase II on the constriction of VSMCs has not yet been investigated. When conducting a natural products screen for an inhibitor against arginase, the present study identified that a relatively high concentration of resveratrol (RSV) exhibited arginase inhibitory activity. Therefore, the present study investigated whether RSV could regulate VSMCs contractions and the underlying mechanism. Arginase inhibition by RSV led to an increase in the concentration of the substrate L-Arg and an accompanying increase in the cytosol Ca 2+ concentration [(Ca 2+ )c] in VSMCs. The increased [Ca 2+ ]c induced by RSV and L-Arg treatments resulted in CaMKII-dependent MLC20 phosphorylation. The effects of RSV on VSMCs were maintained even when VSMCs were pre-treated with sirtinol, an inhibitor of Sirt proteins. In a vascular tension assay with de-endothelialized aortic vessels, vasoconstrictor responses, which were measured using phenylephrine (PE), were significantly enhanced in the RSV-and L-Arg-treated vessels. Therefore, although arginase inhibition has exhibited beneficial effects in various diseases, care is required when considering administration of an arginase inhibitor to patients with vessels endothelial dysfunction as RSV can induce vessel contraction.

Progress in the Preclinical and Clinical Study of Resveratrol for Vascular Metabolic Disease

“…Interestingly, the result from a clinical double-blind randomized trial showed that RSV (1000 mg/day, 8 weeks) could significantly decrease the level of ADMA in patients with diabetes [ 58 ]. Moreover, RSV exhibited arginase inhibitory activity in VSMCs, which led to the accumulation of arginine and the augment of NO production in vascular cells [ 59 ]. Together, RSV could improve amino acid metabolism dysfunction and protect vasculatures from metabolic vascular diseases.…”

Arginase: shedding light on the mechanisms and opportunities in cardiovascular diseases

“…Polyphenols, including resveratrol (RSV), piceatannol (PIC), and (-)-Epicatechin (EPI) perform ARG1 and ARG2 inhibitory activity, which have been investigated for CVDs treatment. RSV, shows arginase inhibitory activity, with inhibition of 38.7 ± 3.1% on liver ARG1 and 32.0 ± 1.3% on kidney ARG2 at 50 µmol/L [ 165 ]. RSV treatment can augment vessel constriction in de-endothelialized aortas [ 165 ], prevent hypoxia-induced human pulmonary artery SMC proliferation, and normalize right ventricular hypertrophy in an in vivo neonatal rat model of pulmonary hypertension [ 166 ].…”

“…RSV, shows arginase inhibitory activity, with inhibition of 38.7 ± 3.1% on liver ARG1 and 32.0 ± 1.3% on kidney ARG2 at 50 µmol/L [ 165 ]. RSV treatment can augment vessel constriction in de-endothelialized aortas [ 165 ], prevent hypoxia-induced human pulmonary artery SMC proliferation, and normalize right ventricular hypertrophy in an in vivo neonatal rat model of pulmonary hypertension [ 166 ]. It has also been reported to exert cardioprotective and vasoprotective effects including anti-atherosclerotic and vasorelaxation action [ 167 ].…”

Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise

“…Resveratrol, a polyphenol found in berries, grapes, and peanuts, has been reported to have anti-leishmanial activity against promastigotes and intracellular amastigotes in vitro [124][125][126][127][128]. It is not known if resveratrol inhibits the Leishmania arginase, however, it appears to inhibit the mammalian arginase [126,129]. Interestingly, resveratrol may exhibit a synergistic effect with amphotericin B against Leishmania promastigotes [126].…”