Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging.
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%.


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.
Dai
Dao-Fu
DF
Department of Pathology, University of Washington, Seattle, 98195, USA.
Santana
Luis F
LF
Vermulst
Marc
M
Tomazela
Daniela M
DM
Emond
Mary J
MJ
MacCoss
Michael J
MJ
Gollahon
Katherine
K
Martin
George M
GM
Loeb
Lawrence A
LA
Ladiges
Warren C
WC
Rabinovitch
Peter S
PS
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D020013:Calcium Signaling; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D003971:Diastole; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000737:chemistry / Q000201:enzymology* / Q000502:physiology; D008955:Models, Cardiovascular; D009154:Mutation; D032383:Myocytes, Cardiac / Q000648:ultrastructure; D050778:NFATC Transcription Factors / Q000032:analysis; D009928:Organ Specificity; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000032:analysis; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000517:prevention & control*
D004272:DNA, Mitochondrial; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D002374:Catalase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse