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(Circulation. 2009;119:2789-2797.)
© 2009 American Heart Association, Inc.

Heart Failure

Overexpression of Catalase Targeted to Mitochondria Attenuates Murine Cardiac Aging

Dao-Fu Dai, MD; Luis F. Santana, PhD; Marc Vermulst, PhD; Daniela M. Tomazela, PhD; Mary J. Emond, PhD; Michael J. MacCoss, PhD; Katherine Gollahon, PhD; George M. Martin, MD; Lawrence A. Loeb, MD, PhD; Warren C. Ladiges, DVM; Peter S. Rabinovitch, MD, PhD

From the Departments of Pathology (D.-F.D., M.V., K.G., G.M.M., L.A.L., P.S.R.), Physiology and Biophysics (L.F.S.), Genome Sciences (D.M.T., M.J.M.), Biostatistics (M.J.E.), and Comparative Medicine (W.C.L.), University of Washington, Seattle.

Correspondence to Peter S. Rabinovitch, MD, PhD, Department of Pathology, University of Washington, 1959 Pacific Ave NE, HSB-K081, Seattle, WA 98195. E-mail petersr{at}u.washington.edu

Received April 22, 2008; accepted March 13, 2009.

Background— Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously shown that overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17% to 21%.

Methods and Results— We used echocardiography to study cardiac function in aging cohorts of wild-type and mCAT mice. Changes found in wild-type mice recapitulate human aging: age-dependent increases in left ventricular mass index and left atrial dimension, worsening of the myocardial performance index, and a decline in diastolic function. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac SERCA2 protein, and activation of the calcineurin–nuclear factor of activated T-cell pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these 2 parameters was 55%.

Conclusions— This study shows that cardiac aging in the mouse closely recapitulates human aging and demonstrates the critical role of mitochondrial reactive oxygen species in cardiac aging and the impact of cardiac aging on survival. These findings also support the potential application of mitochondrial antioxidants in reactive oxygen species–related cardiovascular diseases.

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