Effect of Cystathionine‐Gamma‐Lyase/Hydrogen Sulfide System Modulation on Vascular Dysfunction Induced by Insulin Resistance in Male Wistar Rat Thoracic Aorta

Abstract

Hydrogen sulfide (H2S) is a novel gasotransmitter synthetized from L‐Cysteine by three enzymatic pathways. In blood vessels, cystathionine‐gamma‐lyase (CSE) is mainly expressed and regulates vascular function. This enzyme may be affected by insulin resistance. Insulin resistance leads to vascular dysfunction and is the major mechanism underlying type 2 Diabetes Mellitus. The aim of this study was to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor), L‐Cysteine (L‐Cys; substrate of H2S producing enzymes) and DL‐Propargylglycine (DL‐PAG; CSE inhibitor) on the vascular dysfunction induced by insulin resistance in male Wistar rat thoracic aorta. For that purpose, animals were divided into two main sets that received for 20 weeks: (1) tap water (control group; n=6); and (2) 15% p/v fructose in drinking water (insulin resistance group; n=30). Then, the insulin resistance group were divided into 5 subgroups (n=6 each) which received daily i.p. injections during 4 weeks of: (1) nothing (without pharmacological administration); (2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); (3) NaHS (5.6 mg/kg); (4) L‐Cys (300 mg/kg); and (5) DL‐PAG (10 mg/kg). After 20 weeks, metabolic (oral glucose tolerance test, plasma insulin levels, and Matsuda‐index) and hemodynamics variables by tail‐cuff method as well as vascular function by in vitro experiments were determined. Fructose‐induced insulin resistance leads to: (1) hypertension (without affecting heart rate); (2) hyperinsulinemia; (3) a decrease in Matsuda‐index; and (4) a decrease in carbachol‐induced vasorelaxant responses with no effect on the contractile responses to noradrenaline. Interestingly, after 4 weeks of treatment, NaHS decreased blood pressure and restored vasorelaxant responses to carbachol with no effect on metabolic variables while L‐Cys improved the contractile and vasorelaxant responses to noradrenaline and carbachol, respectively, when compared to vehicle (PBS). On the other hand, DL‐PAG induced a slightly increase in systolic and median blood pressure with no effect on the contractile response to noradrenaline or relaxant responses to carbachol as well as metabolic variables compared to vehicle. Taken together, these results suggest that chronic treatment with NaHS and L‐Cys improved vascular dysfunction and hypertension induced by insulin resistance and may have a potential therapeutic application.Support or Funding InformationThe authors acknowledge to Conacyt (Grant No. 252702) for its financial support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.