Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy.
Thioredoxin 1 (Trx1) has redox-sensitive cysteine residues and acts as an antioxidant in cells. However, the extent of Trx1 contribution to overall antioxidant mechanisms is unknown in any organs. We generated transgenic mice with cardiac-specific overexpression of a dominant negative (DN) mutant (C32S/C35S) of Trx1 (Tg-DN-Trx1 mice), in which the activity of endogenous Trx was diminished. Markers of oxidative stress were significantly increased in hearts from Tg-DN-Trx1 mice compared with those from nontransgenic (NTg) mice. Tg-DN-Trx1 mice exhibited cardiac hypertrophy with maintained cardiac function at baseline. Intraperitoneal injection of N-2-mercaptopropionyl glycine, an antioxidant, normalized cardiac hypertrophy in Tg-DN-Trx1 mice. Thoracic aortic banding caused greater increases in myocardial oxidative stress and enhanced hypertrophy in Tg-DN-Trx1 compared with NTg mice. In contrast, transgenic mice with cardiac-specific overexpression of wild-type Trx1 did not show cardiac hypertrophy at baseline but exhibited reduced levels of hypertrophy and oxidative stress in response to pressure overload. These results demonstrate that endogenous Trx1 is an essential component of the cellular antioxidant mechanisms and plays a critical role in regulating oxidative stress in the heart in vivo. Furthermore, inhibition of endogenous Trx1 in the heart primarily stimulates hypertrophy, both under basal conditions and in response to pressure overload through redox-sensitive mechanisms.
Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Medical Science Building G-609, Newark, New Jersey 07103, USA. Sadoshju@umdnj.edu
Mitsutaka
M
Yamamoto
Guiping
G
Yang
Chull
C
Hong
Jing
J
Liu
Eric
E
Holle
Xianzhong
X
Yu
Thomas
T
Wagner
Stephen F
SF
Vatner
Junichi
J
Sadoshima
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D018384:Oxidative Stress; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases
D013879:Thioredoxins; D002374:Catalase; D013482:Superoxide Dismutase; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases