Submitted on October 13, 2008
Revised on December 31, 2008
Accepted on January 15, 2009
The Role of Angiotensin II and Oxidative Stress in Vascular Insulin Resistance Linked to Hypertension
Ming-Sheng Zhou1*, Ivonne Hernandez Schulman2, and Leopoldo Raij3
1 University of Miami
2 Veterans Affairs Medical Center
3 University of Miami School of Medicine
* To whom correspondence should be addressed. E-mail: MZhou2{at}med.miami.edu.
Insulin activation of the phosphatidylinositol 3-kinase (PI3K) pathway stimulates glucose uptake in peripheral tissues and synthesis of nitric oxide (NO) in the endothelium. Insulin resistance (IR) and hypertension frequently coexist particularly among individuals with salt-sensitive (SS) hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of SS hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide (O2-) linked to local angiotensin II. Dahl SS rats were fed for 6 weeks a normal salt (NS, 0.5% NaCl) or high salt (HS, 4% NaCl) diet, HS plus angiotensin II type 1 receptor (AT1R) blocker candesartan (ARB, 10 mg/kg/day), or HS plus antioxidant Tempol (172 mg/L in the drinking water). Hypertensive (mean arterial pressure (MAP): 145±4 vs. 102±5mmHg in NS, P<0.05) rats manifested increased aortic AT1R mRNA (210%) and protein (101%) expression and O2- production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine (Emax: 68±9 vs. 91±8% in NS, P<0.05). ARB or Tempol normalized O2- and EDR despite a small MAP reduction (-25%). Hypertensive rats manifested metabolic IR (36% reduction in glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR (Emax: 12±5 vs. 32±4% in NS, P<0.05), and impaired insulin activation of PI3K/eNOS. ARB or Tempol improved insulin-mediated EDR, PI3K, Akt/eNOS phosphorylation and metabolic IR (all P<0.05). These studies provide insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that O2- overproduction linked to tissue angiotensin II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.
