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...

The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47 phox and p67 phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47 phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells.Insulin resistance and hypertension often coexist and frequently progress to diabetes and cardiovascular disease (1, 2). A reduced response by target tissues to insulin (3) is the hallmark of the metabolic syndrome (1-5), which is defined by a cluster of abnormalities including impaired glucose tolerance, hypertension, abdominal obesity, and dyslipidemia (6). Insulin signaling is a complex process involving multiple pathways and phosphorylation events. Phosphorylation of protein kinase B (Akt) is a key step leading to the translocation of glucose transporter 4 (GLUT4) 2 from intracellular compartments to the plasma membrane. GLUT4 helps mediate the increase in glucose uptake in skeletal muscle and adipose tissues in the presence of insulin (7,8). Skeletal muscle insulin receptor signaling is defective in metabolic syndrome and type 2 diabetes mellitus (T2DM) both in experimental models and humans (1-6;9). Many factors have been reported to induce insulin resistance in vitro and in vivo, including angiotensin II (Ang II), tumor necrosis factor (TNF)-␣, interleukin 6 (IL-6), and free fatty acids (10 -13).Ang II is an important physiological regulator of blood pressure, cardiac function, and salt and fluid homeostasis. Its hypertensive, growth, and remodeling effects are mediated through the Ang II receptor 1 (AT 1 R) (1, 5, 11). In addition, Ang II appears to be antagonistic to insulin action and contributes to insulin resistance. Several prospective clinical studies have shown that treating hypertensive patients with angiote...

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Women are especially predisposed to development of arterial stiffening secondary to obesity due to consumption of excessive calories. Enhanced activation of vascular mineralocorticoid receptors impairs insulin signaling, induces oxidative stress, inflammation and maladaptive immune responses. We tested whether a sub-pressor dose of mineralocorticoid receptor antagonist, spironolactone (1 mg•kg−1•day−1) prevents aortic and femoral artery stiffening in female C57BL/6J mice fed a high fat/high sugar western diet (WD) for four months (i.e., from 4–20 weeks of age). Aortic and femoral artery stiffness were assessed using ultrasound, pressurized vessel preparations and atomic force microscopy. WD induced weight gain and insulin resistance compared to control diet-fed mice and these abnormalities were unaffected by spironolactone. Blood pressures and heart rates were normal and unaffected by diet or spironolactone. Spironolactone prevented WD-induced stiffening of aorta and femoral artery as well as endothelial and vascular smooth muscle cells within aortic explants. Spironolactone prevented WD-induced impaired aortic protein kinase B/endothelial nitric oxide synthase signaling, as well as, impaired endothelium-dependent and –independent vasodilation. Spironolactone ameliorated WD-induced aortic medial thickening and fibrosis and the associated activation of the pro-growth extracellular receptor kinase 1/2 pathway. Finally, preservation of normal arterial stiffness with spironolactone in WD-fed mice was associated with attenuated systemic and vascular inflammation and an anti-inflammatory shift in vascular immune cell marker genes. Low-dose spironolactone may represent a novel prevention strategy to attenuate vascular inflammation, oxidative stress, and growth pathway signaling and remodeling to prevent development of arterial stiffening secondary to consumption of a WD.