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...

Obese and diabetic individuals are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction. The impairments in diastolic relaxation are especially pronounced in obese and diabetic women and predict future cardiovascular disease (CVD) events in this population. Recent clinical data suggest sodium glucose transporter-2 (SGLT2) inhibition reduces CVD events in diabetic individuals, but the mechanisms of this CVD protection are unknown. To determine whether targeting SGLT2 improves diastolic relaxation, we utilized empagliflozin (EMPA) in female db/db mice. Eleven week old female db/db mice were fed normal mouse chow, with or without EMPA, for 5 weeks. Blood pressure (BP), HbA1c and fasting glucose were significantly increased in untreated db/db mice (DbC) (P < 0.01). EMPA treatment (DbE) improved glycemic indices (P < 0.05), but not BP (P > 0.05). At baseline, DbC and DbE had already established impaired diastolic relaxation as indicated by impaired septal wall motion (>tissue Doppler derived E′/A′ ratio) and increased left ventricular (LV) filling pressure (

Rationale Enhanced activation of the mineralocorticoid receptors (MR) in cardiovascular tissues increases oxidative stress, maladaptive immune responses and inflammation with associated functional vascular abnormalities. We previously demonstrated that consumption of a Western Diet (WD) for 16 weeks results in aortic stiffening, and that these abnormalities were prevented by systemic MR blockade in female mice. However, the cell specific role of endothelial MR (ECMR) in these maladaptive vascular effects has not been explored. Objective We hypothesized that specific deletion of the ECMR would prevent WD-induced increases in endothelial sodium channel (ENaC) activation, reductions in bioavailable nitric oxide (NO), increased vascular remodeling and associated increases in vascular stiffness in females. Methods and Results Four week-old female ECMR knockout and wild type mice were fed either mouse chow or WD for 16 weeks. WD feeding resulted in aortic stiffness and endothelial dysfunction as determined in vivo by pulse wave velocity (PWV) and ex vivo by atomic force microscopy, and wire and pressure myography. The WD-induced aortic stiffness was associated with enhanced ENaC activation, attenuated endothelial NO synthase (eNOS) activation, increased oxidative stress, a pro-inflammatory immune response and fibrosis. Conversely, cell specific ECMR deficiency prevented WD-induced aortic fibrosis and stiffness in conjunction with reductions in ENaC activation, oxidative stress and macrophage pro-inflammatory polarization, restoration of eNOS activation. Conclusions Increased ECMR signaling associated with consumption of a WD plays a key role in endothelial ENaC activation, reduced NO production, oxidative stress, and inflammation that lead to aortic remodeling and stiffness in female mice.

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.