Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes.
Oxidative stress contributes to diabetic cardiomyopathy. This study explored the role of the NADPH oxidase Nox4 as a source of reactive oxygen species (ROS) involved in the development of diabetic cardiomyopathy. Phosphorothioated antisense (AS) or sense (S) oligonucleotides for Nox4 were administered for 2 wk to rats made diabetic by streptozotocin. NADPH oxidase activity, ROS generation, and the expression of Nox4, but Nox1 or Nox2, were increased in left ventricular tissue of the diabetic rats. Expression of molecular markers of hypertrophy and myofibrosis including fibronectin, collagen, α-smooth muscle actin, and β-myosin heavy chain were also increased. These parameters were attenuated by the administration of AS but not S Nox4. Moreover, the impairment of contractility observed in diabetic rats was prevented in AS- but not S-treated animals. Exposure of cultured cardiac myocytes to 25 mM glucose [high glucose (HG)] increased NADPH oxidase activity, the expression of Nox4, and molecular markers of cardiac injury. These effects of HG were prevented in cells infected with adenoviral vector containing a dominant negative form of Nox4. This study provides strong evidence that Nox4 is an important source of ROS in the left ventricle and that Nox4-derived ROS contribute to cardiomyopathy at early stages of type 1 diabetes.
Dept. of Medicine, Division of Cardiology, Univ. of Texas Health Science Center, San Antonio, TX 78229-3900, USA. rita.maalouf@ndu.edu.lb
Rita M
RM
Maalouf
Assaad A
AA
Eid
Yves C
YC
Gorin
Karen
K
Block
Gladys Patricia
GP
Escobar
Steven
S
Bailey
Hanna E
HE
Abboud
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000096:biosynthesis; D005947:Glucose / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024723:Ventricular Myosins / Q000096:biosynthesis
D000199:Actins; D005353:Fibronectins; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D003094:Collagen; D009247:NADH, NADPH Oxidoreductases; C500593:Cybb protein, rat; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat; C498911:Nox4 protein, rat; D024723:Ventricular Myosins; D005947:Glucose