Effect of Retinoic Acid in Improving Endothelium Dependent Vascular Reactivity in Hyperhomocysteinemic Rats

Author(s):

Shivali Singla*, Sachin Goyal, Raveena Devi, Shalini Jamwal and Saurabh Sharma

Introduction: Retinoic acid is a metabolite of Vitamin A (retinol) has been reported to activate PI3K/Akt pathway and up regulate NO synthesis that has a beneficial effect in the endothelial cell. Thus, the present study was designed to investigate the effect of retinoic acid in HHcy induced vascular dysfunction.

Objective: This study evaluates the protective effect of retinoic acid on L-methionine-induced Hyperhomocysteinemia (HHcy) in rats.

Materials and methods: Wistar rats were randomly divided into seven groups as normal control, L-methionine, HHcy+Retinoic acid (2.5 mg/kg/d), HHcy+RA (5 mg/kg/d), HHcy+RA (5 mg/kg/d) + BEZ235 (4 mg/kg/d), HHcy+RA (5 mg/kg/d)+L-NAME (10 mg/kg/d), HHcy+Lisinopril (1 mg/ kg./d). HHcy was induced by oral administration of L-methionine (1.7 g/kg) for 28 days. From the 21^st day of study retinoic acid (2, 2.5 mg/kg), BEZ235, L-NAME, Lisinopril was administered to L-methionine-treated rats. Different biomarkers of HHcy in serumand vascular reactivity were evaluated.

Results: L-methionine administration, vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-inducedendothelium-dependent relaxation (Isolated aortic ring preparation), a decrease in serum nitrite level, mRNA expression of eNOS (rtPCR). Administration of retinoic acid (2.5 mg/kg/d and 5 mg/kg/d, 21^st to 28^th day) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS. This ameliorative effect of retinoic acid was blocked by BEZ235 (a PI3K /mTOR dual inhibitor) and L-NAME (NOS inhibitor).

Conclusion: Retinoic acid attenuates hyperhomocysteinemia induced vascular endothelium dysfunction in Wistar rats by activation of PI3K/mTOR and eNOS pathway.