Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension

Ming Sheng Zhou, Ivonne Hernandez Schulman, Leopoldo Raij

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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 hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of salt-sensitive hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide anion (O-) linked to local ANG II. Dahl salt-sensitive rats were fed, for 6 wk, a normal salt diet (NS; 0.5% NaCl), high-salt diet (HS; 4% NaCl), HS plus the ANG II type 1 receptor (AT1R) blocker (ARB) candesartan (10 mg• kg -1 • day -1), or HS plus the antioxidant tempol (172 mg/l in drinking water). Hypertensive (mean arterial pressure: 145 ±; 4 vs. 102 ±; 5 mmHg in NS, P < 0.05) rats manifested increased aortic AT1R mRNA (210%) and protein (101%) expression and O- production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response (E max): 68 ±; 9 vs. 91 ±; 8% in NS, P < 0.05]. ARB or tempol normalized O- and EDR despite that they did not normalize mean arterial pressure, which was reduced only 25%. Hypertensive rats manifested metabolic IR (36% reduction in the glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR (E max:12 ±; 5 vs. 32 ±; 4% in NS, P < 0.05), and impaired insulin activation of PI3K/endothelial NO synthase. ARB or tempol improved insulin-mediated EDR, PI3K, Akt/ endothelial NO synthase phosphorylation, and metabolic IR (all P < 0.05). This study provides insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that O 2- overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.

Original languageEnglish (US)
Pages (from-to)H833-H839
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number3
DOIs
StatePublished - Mar 1 2009

Keywords

  • Endothelial function
  • Salt sensitivity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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