Glutaredoxin 1 overexpression inhibits JNK activity and ameliorates myocyte apoptosis and progression to heart failure in Galphaq overexpressing transgenic mice

Background Glutaredoxin 1 (Grx1), an antioxidant enzyme, plays an important role in protecting cells from oxidative stress and apoptosis, events associated with myocardial remodeling and failure. Transgenic mice with cardiac-specific overexpression of Gαq develop a dilated cardiomyopathy. In the present study, we examined the effects of Grx1 on myocardial remodeling and failure and the underlying mechanism. Methods Gαq mice were cross-bred with transgenic mice having overexpression of Grx1, and the resulting mice were followed 20 weeks by echocardiography (n=7-21 per group). Exercise stress test was performed on a motorized treadmill at 20 weeks. Results In Gαq mice compared with wild-type (WT) mice, left ventricular (LV) end-diastolic dimension (EDD) was increased and LV fractional shortening (FS) was decreased at 4 weeks, and progressively deteriorated through 20 weeks. Grx1 overexpression in Gαq mice had no effect on EDD or FS at 4 weeks, but attenuated the subsequent changes in EDD and FS over weeks 12 through 20. At 20 weeks, maximal exercise capacity was decreased by 40% in Gαq mice (273±36 vs. 456±38 meters in WT, P Conclusion In Gαq mice, Grx1 overexpression had no effect on the initial phenotype of LV dilation and dysfunction but prevented the subsequent progressive remodeling and heart failure via suppression of oxidative stress, JNK activity and myocyte apoptosis. The findings indicate that Grx1 may be a potential therapeutic target for adverse LV remodeling and progression to failure.