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

Abstract

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 2ϩ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR 90 ), maximal velocity of shortening/relengthening (ϮdL/dt), and intracellular Ca 2ϩ decay (). HG myocytes exhibited normal PS; decreased ϮdL/dt; and prolonged TPS, TR 90 , and . 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 mol/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 mol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 mol/L) or apocynin (100 mol/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.

Is Cardiac Hypertrophy in Spontaneously Hypertensive Rats the Cause or the Consequence of Oxidative Stress?

“…It acts by impeding the assembly of the p47-phox and p67-phox subunits within the membrane NAD(P)H oxidase complex (56,57). Some of the effects of apocynin treatment are protection of the endothelium from the initiating events of atherosclerosis (57), a reduction of p22-phox mRNA expression and cardiac hypertrophy in aldosterone-infused rats (58), and a prevention of hyperglycemia-induced intracellular ROS elevation and myocyte dysfunction (59). Aponycin has also been shown to reduce oxidative stress in stroke-prone spontaneously hypertensive rats, leading to the suppression of cardiac hypertrophy, inflammation and fibrosis (60).…”

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

“…Our earlier study revealed that angiotensin receptormediated activation of NADPH oxidase plays a role in hyperglycaemia-induced cardiac dysfunction [34]. (Fig.…”

Retracted: Activation of Akt Rescues Endoplasmic Reticulum Stress-Impaired Murine Cardiac Contractile Function via Glycogen Synthase Kinase-3β-Mediated Suppression of Mitochondrial Permeation Pore Opening

“…In brief, isolated cardiomyocytes from WT and MyAkt mice were incubated with tunicamycin (3 lg/ml) at 37°C for 5-6 h. A cohort of WT cardiomyocytes were coincubated with the ER stress inhibitor TUDCA (500 lM), or the antioxidant catalase-PEG (15,000 IU/ml) (36) at the same time with tunicamycin. H 2 O 2 (100 lM) was used as the positive control in the absence or presence of the antioxidant catalase-PEG.…”