Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance

Abstract

JR. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol 293: H2009 -H2023, 2007. First published June 22, 2007; doi:10.1152/ajpheart.00522.2007.-Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/ IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue.HYPERTENSION is present in ϳ30% of the adult United States population and often occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome (CMS) (29,115,163,186,190). According to recent data, up to 70 million Americans have insulin resistance, which plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease (CKD), and cardiovascular (CV) disease (CVD) (69). There is accumulating evidence that insulin resistance occurs in CV and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue) (125,186,190). This review focuses on currently accepted mechanisms underlying the development of resistance to the metabolic actions of insulin in CV tissue (see Figs. 1 and 2) as well as skeletal muscle tissues (27,190) (see Fig. 3). Normal Actions of Insulin in CV TissueBoth insulin and IGF-1 receptors exist in CV tissue (186). Upon binding to specific receptors, they activate a number of downstream signaling systems that result in vasorelaxation (125, 188 -191) and myocardial glucose uptake and alteration of cardiac energy homeostasis (125,186,190). Activation of the insulin receptor (IR) and IGF-1 receptor, ligand-activated transmembrane receptors with tyrosine kinase activity, phosphorylates intracellular substrates including IR substrate (IRS) family members and Shc, which, in turn, serve as docking proteins for downstream signaling molecules (27,125). IRS phosphorylation of tyrosine moieties results in the engagement of Src homology 2 (SH2) domain-binding motifs for SH2 domain signaling molecules, including phosphatidyl 3-kinase (PI3K) and Grb-2. When SH2 domains of the p85 regulatory subunit bind to tyrosine-phosphorylated motifs on IRS-1, this activates the preassociated p110 catalytic subunit to generate phosph...

Non-dipping pattern relates to endothelial dysfunction in patients with uncontrolled resistant hypertension

“…Thus, by mineralocorticoid receptor activation, glucocorticoids promote inflammation, oxidative stress, fibrosis, insulin resistance and also endothelial dysfunction. [45][46][47] Moreover, because of insulin resistance, there is decreased insulin stimulation of endothelial NO synthase activation and increased NO destruction. 43 Our results clearly reveal a significant association between RHTN, non-dipping BP and endothelial dysfunction.…”

Matsuda–DeFronzo insulin sensitivity index is a better predictor than HOMA-IR of hypertension in Japanese: the Tanno–Sobetsu study

“…5,[47][48][49] Thus, the finding that association of ISI-M with new-onset hypertension in the multiple logistic regression analysis was lost by incorporating BMI as a dependent variable (Table 4) does not necessarily exclude the possibility that IR per se contributes to the development of hypertension. In fact, OR of hypertension was higher in a subgroup with lower ISI-M than in a subgroup with higher ISI-M for each tertile of BMI in subjects o60 years old (Figure 3), whereas higher BMI was associated with higher OR of hypertension.…”

Free Fatty Acid Causes Leukocyte Activation and Resultant Endothelial Dysfunction Through Enhanced Angiotensin II Production in Mononuclear and Polymorphonuclear Cells

“…This hypothesis appears plausible because of the close relationship between obesity and RAS activity in humans. 10,11 In addition, RAS activation is also associated with enhanced oxidative stress, 12 which is an intermediary mechanism by which FFA adversely alters vascular function. 13 However, although the proatherogenic action of excessive Ang II has been well documented, there is little information regarding the mechanism of RAS activation in individuals with obesity.…”