Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers

Abstract

Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demonstrated that the nitric oxide (NO) synthase (NOS) genes are critically involved in the regulation of insulin-mediated glucose disposal. The generation of NO by the NOS enzymes is known to contribute to vascular homeostasis including insulin-mediated skeletal muscle vasodilation and insulin sensitivity. By contrast, excessive inhibition of NOS enzymes by exogenous or endogenous factors is associated with insulin resistance (IR). Asymmetric dimethylarginine (ADMA) is an endogenous molecule that competitively inhibits all the NOS enzymes and contributes to metabolic perturbations including IR. The concentration of ADMA in plasma and tissue is enzymatically regulated by dimethylarginine dimethylaminohydrolase (DDAH), a widely expressed enzyme in the cardiovascular system. In preclinical studies, overexpression of DDAH has been shown to reduce ADMA levels, improve vascular compliance, and increase insulin sensitivity. This review discusses the feasibility of the NOS/DDAH pathway as a novel target to develop vasoprotective insulin sensitizers.

Strict glucose control and artificial regulation of the NO–ADMA–DDAH system in order to prevent endothelial dysfunction

“…; Siroen et al . ; Lai & Ghebremariam, ). These diseases are often associated with hyperglycaemia as a consequence of IR.…”

“…Low levels of intracellular glucose diminish or even eliminate enzyme systems such as the NOS–ADMA–DDAH pathway (Lin et al . ; Lai & Ghebremariam, ). As consequence, IR results in a disturbed NO metabolism and subsequent endothelial dysfunction in the vascular wall, manifested by impaired endothelium‐dependent vasodilatation.…”

“…For instance, it might also be necessary to modulate DDAH enzymatic activity by chemical entities and transcriptional DDAH regulators that upregulate the gene expression of DDAH and downregulate ADMA, e.g. metformin, thiazolidinediones, sulfonylurea, INT‐747, GW4064 and vitamin A (Lai & Ghebremariam, ). Providing the precursors of arginine, such as glutamine, and decreasing arginase production by giving an arginase inhibitor could also be an effective strategy.…”

Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders

“…Its nitrosylation by reactive nitrogen species renders the enzyme inactive which can be the potential homeostatic mechanism especially in reactions involving the inducible NOS (iNOS) (increased production of NO leads to the accumulation of ADMA by inhibiting the DDAH) [39] (Figure 2). In addition, this cysteine residue is susceptible to the action of the number of oxidative stressrelated cardiovascular risk factors such as hypercholesterolemia, hypertension, renal failure [41], hyperhomocysteinemia, hyperglycaemia [42], and tobacco smoking [43], which also results in the accumulation of ADMA. This can be a pathway, allowing different factors to affect endothelial function [44].…”

Vascular Aging: Implications for Cardiovascular Disease and Therapy

“…In mammalian cells, three isoforms of NOS are differentially expressed in neurons (neuronal NOS; nNOS), immune cells (inducible NOS; iNOS) and vascular cells (endothelial NOS; eNOS) [ 48 – 50 ]. In the cardiovascular system, eNOS is a multisubstrate enzyme and plays a significant role in catalyzing the production of NO from its substrate L-arginine in the presence of cosubstrates and cofactors [ 49 ].…”