Regulation of Endothelial Nitric Oxide Synthase and High-Density Lipoprotein Quality by Estradiol in Cardiovascular Pathology

Abstract

Estrogens have been recognized, in the last 3 decades, as important hormones in direct and indirect modulation of vascular health. In addition to their direct benefit on cardiovascular health, the presence of esterified estrogen in the lipid core of high-density lipoprotein (HDL) particles indirectly contributes to atheroprotection by significantly improving HDL quality and functionality. Estrogens modulate their physiological activity via genomic and nongenomic mechanisms. Genomic mechanisms are thought to be mediated directly by interaction of the hormone receptor complex with the hormone response elements that regulate gene expression. Nongenomic mechanisms are thought to occur via interaction of the estrogen with membrane-bound receptors, which rapidly activate intracellular signaling without binding of the hormone receptor complex to its hormone response elements. Estradiol in particular mediates early and late endothelial nitric oxide synthase (eNOS) activation via interaction with estrogen receptors through both nongenomic and genomic mechanisms. In the vascular system, the primary endogenous source of nitric oxide (NO) generation is eNOS. Nitric oxide primarily influences blood vessel relaxation, the heart rate, and myocyte contractility. The abnormalities in expression and/or functions of eNOS lead to the development of cardiovascular diseases, both in animals and in humans. Although considerable research efforts have been dedicated to understanding the mechanisms of action of estradiol in regulating cardiac eNOS, more research is needed to fully understand the details of such mechanisms. This review focuses on recent findings from animal and human studies on the regulation of eNOS and HDL quality by estradiol in cardiovascular pathology.

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

“…Nitric oxide (NO) plays an important role in cardiovascular function by regulating relaxation of blood vessels and also influencing cardiomyocyte contractility (Moncada, Higgs 1995, Kypreos et al 2014. Endogenously, NO is released as a product during conversion of the amino acid Larginine (L-arg) to L-citrulline in a reaction mediated by NOS (Stanimirovic et al 2015, SudarMilovanovic et al 2015.…”

“…Overproduction of NO as a result of inducible NOS (iNOS) activation leads to reduced myocardial contractility and also has detrimental effects to the heart (Ikeda, Shimada 1997). E 2 exerts many of its effects in cardiomyocytes through activation of the insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) signalling cascades (Kypreos et al 2014, Obradovic et al 2014). E 2 exerts beneficial effects on the cardiovascular system by reducing nuclear factor kappa-B (NFkB), IkB and iNOS expression during ischemia (Karpuzoglu, Ahmed 2006).…”

“…Endogenously, NO is released as a product during conversion of the amino acid Larginine (L-arg) to L-citrulline in a reaction mediated by NOS (Stanimirovic et al 2015, SudarMilovanovic et al 2015. The primary source of NO generation in the vascular system is endothelial NOS (Rhodes et al 1995, Kypreos et al 2014). Overproduction of NO as a result of inducible NOS (iNOS) activation leads to reduced myocardial contractility and also has detrimental effects to the heart (Ikeda, Shimada 1997).…”

Effects of altered hepatic lipid metabolism on regulation of hepatic iNOS

“…Nitric oxide, one of the smallest known bioactive product of mammalian cells, is an important, highly reactive signaling molecule involved in many physiological and pathological processes [10,26]. It is biosynthesized by three distinct isoforms of NOS enzyme: nNOS, eNOS and iNOS [10,26].…”

“…It is biosynthesized by three distinct isoforms of NOS enzyme: nNOS, eNOS and iNOS [10,26]. All three isoforms of NOS enzyme are expressed in the liver [27], but unlike eNOS and nNOS, which are constitutively expressed in physiological condition, iNOS is expressed when stimulated by different factors including inflammation and oxidative stress [11,[28][29].…”