title: AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase.
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 (AT1) 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 Ca2+ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening (+/-dL/dt), and intracellular Ca2+ decay (tau). HG myocytes exhibited normal PS; decreased +/-dL/dt; and prolonged TPS, TR90, and tau. Interestingly, the HG-induced abnormalities were prevented with the AT1 blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 micromol/L). The only effect of AT1 blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT1 antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 micromol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 micromol/L) or apocynin (100 micromol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47phox and the AT1 but not the AT2 receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47phox was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT1 blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT1 receptor-mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, USA.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Privratsky
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006331:Heart Diseases / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D053614:Janus Kinase 2; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology*; D010750:Phosphoproteins / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis / Q000502:physiology*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D057911:Angiotensin Receptor Antagonists; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D012967:Sodium Dodecyl Sulfate; C070967:L 158809; C056165:acetovanillone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D005947:Glucose