Hydrogen Sulfide Releasing Aspirin, ACS14, Attenuates High Glucose-Induced Increased Methylglyoxal and Oxidative Stress in Cultured Vascular Smooth Muscle Cells

Abstract

Hydrogen sulfide is a gasotransmitter with vasodilatory and anti-inflammatory properties. Aspirin is an irreversible cyclooxygenase inhibitor anti-inflammatory drug. ACS14 is a novel synthetic hydrogen sulfide releasing aspirin which inhibits cyclooxygenase and has antioxidant effects. Methylglyoxal is a chemically active metabolite of glucose and fructose, and a major precursor of advanced glycation end products formation. Methylglyoxal is harmful when produced in excess. Plasma methylglyoxal levels are significantly elevated in diabetic patients. Our aim was to investigate the effects of ACS14 on methylglyoxal levels in cultured rat aortic vascular smooth muscle cells. We used cultured rat aortic vascular smooth muscle cells for the study. Methylglyoxal was measured by HPLC after derivatization, and nitrite+nitrate with an assay kit. Western blotting was used to determine NADPH oxidase 4 (NOX4) and inducible nitric oxide synthase (iNOS) protein expression. Dicholorofluorescein assay was used to measure oxidative stress. ACS14 significantly attenuated elevation of intracellular methylglyoxal levels caused by incubating cultured vascular smooth muscle cells with methylglyoxal (30 µM) and high glucose (25 mM). ACS14, but not aspirin, caused a significant attenuation of increase in nitrite+nitrate levels caused by methylglyoxal or high glucose. ACS14, aspirin, and sodium hydrogen sulfide (NaHS, a hydrogen sulfide donor), all attenuated the increase in oxidative stress caused by methylglyoxal and high glucose in cultured cells. ACS14 prevented the increase in NOX4 expression caused by incubating the cultured VSMCs with MG (30 µM). ACS14, aspirin and NaHS attenuated the increase in iNOS expression caused by high glucose (25 mM). In conclusion, ACS14 has the novel ability to attenuate an increase in methylglyoxal levels which in turn can reduce oxidative stress, decrease the formation of advanced glycation end products and prevent many of the known deleterious effects of elevated methylglyoxal. Thus, ACS14 has the potential to be especially beneficial for diabetic patients pending further in vivo studies.

Interaction of Hydrogen Sulfide with Nitric Oxide in the Cardiovascular System

“…However, Huang et al found that treatment with NaHS or H 2 S releasing donor, ACS14, for 24 h attenuated the increase in iNOS expression caused by high glucose (25 mM). This is similar to the inhibitory effect of H 2 S on iNOS expression in heart [ 134 ]. These data suggest that H 2 S may regulate iNOS expression in a time-dependent manner.…”

“…They are accompanied by oxidative stress, which is the result of imbalance between ROS generating and ROS-scavenging systems [ 145 – 147 ]. It is now a well-established fact that ROS generation is ramped up in heart [ 134 ] and blood vessels [ 135 ] during cardiovascular pathologies. Oxidative stress is a result of excessive production of ROS like O 2 − , • HO, H 2 O 2 , NO, ONOO − , and HClO, mainly as a byproducts of cellular aerobic metabolism.…”

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

“…MGO increases arginase expression in endothelial cells and vascular smooth muscle cells (VSMCs) (141). ROS promote the pathological elevation of arginase; however, whether MGO-induced oxidative stress in endothelial cells and VSMCs (103,245,609,610) is involved in the MGO-induced increased expression of arginase remains to be determined. In VSMCs, MGO also decreases hydrogen sulfide levels (102).…”

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

“…This compound has gastric H 2 S Donors and H 2 S Biosynthesis Inhibitors mucosa sparing properties (Sparatore et al, 2009) as well as antihypertensive, vascular protective effects, and protective effects against myocardial ischemiareperfusion in rodent models (Rossoni et al, 2010). ACS14 also protects microglial cells from amyloidb-peptide-induced cytotoxicity (Liu et al, 2011b), protects endothelial cells against methylglyoxal-induced dysfunction (Huang et al, 2014), and inhibits platelet aggregation and exerts antithrombotic effects in vitro and in vivo (Pircher et al, 2012;Gao et al, 2015). One of the problems with the available literature with ACS14 is that head-to-head comparisons with aspirin are sometimes missing (e.g., Giustarini et al, 2010) or sometimes the comparisons are difficult to evaluate.…”