AT 1 Blockade Prevents Glucose-Induced Cardiac Dysfunction in Ventricular Myocytes

Abstract

Enhanced tissue angiotensin (Ang) II levels have been reported in diabetes and might lead to cardiac dysfunction through oxidative stress. This study examined the effect of blocking the Ang II type 1 (AT 1 ) receptor on high glucose–induced cardiac contractile dysfunction. Rat ventricular myocytes were maintained in normal- (NG, 5.5 mmol/L) or high- (HG, 25.5 mmol/L) glucose medium for 24 hours. Mechanical and intracellular Ca 2+ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR 90 ), maximal velocity of shortening/relengthening (± dL / dt ), and intracellular Ca 2+ decay (τ). HG myocytes exhibited normal PS; decreased ± dL / dt ; and prolonged TPS, TR 90 , and τ. Interestingly, the HG-induced abnormalities were prevented with the AT 1 blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 μmol/L). The only effect of AT 1 blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT 1 antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 μmol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 μmol/L) or apocynin (100 μmol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47 phox and the AT 1 but not the AT 2 receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47 phox was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT 1 blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT 1 receptor–mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.