Abstract 13725: Oxidative Stress Accelerates Senescence and Reduces Life Span but Does Not Alter Cardioprotection in Mice Over-expressing H11kinase/hsp22
H11 kinase/Hsp22 (H11K) is a small heat shock protein which provides powerful cardioprotection, i.e., reduction by 80% of infarct size expressed as a fraction of area at risk following 45 min coronary occlusion/4 hr reperfusion when over-expressed in a cardiac-specific transgenic (TG) mouse model. The goal of this investigation was to determine if these protective mechanisms would also enhance longevity and be effective in protecting from age-related myocardial dysfunction. Surprisingly, TG mice showed a reduction of 48% in their mean life span as compared to wild type (WT). The mechanism of premature death was most likely cardiac as left ventricular ejection fraction was reduced in one year old TG mice (49% vs 74% in WT, p<0.01), left ventricular cavity was dilated and cardiac hypertrophy was increased by 58%, all compatible with severe dilated cardiomyopathy. At the molecular level, hearts from TG mice showed a significant increase in reactive oxygen species, oxidized/reduced glutathione ratio, NADPH and xanthine oxidase activities, Nox2 expression associated with an increase in p16, p19 mRNA, β-galactosidase positive cells and telomerase activity. Subgroups of WT and TG mice were also treated with the antioxidant tempol (100 mg/kg/d) from weaning to their sacrifice. Chronic tempol treatment abolished oxidative stress, reduced cardiac hypertrophy, extended life span (+31%) and prevented aging markers (p16, p19 mRNA, β-galactosidase positive cells) in TG mice. The marked reduction in infarct size with ischemia/reperfusion noted above, observed in 10-12 weeks old mice, remained unchanged after tempol in TG mice and was not abolished with aging. Thus, this is the first demonstration that the mechanisms mediating reduced longevity such as increased oxidative stress do not reduce cardioprotection in H11K TG mice, and conversely, the mechanisms mediating powerful cardioprotection against ischemic stress are ineffective in maintaining normal cardiac function with aging.
Author Disclosures: D. Morin: None. R. Long: None. L. Laure: None. C. Depre: None. S.F. Vatner: None. D.E. Vatner: None. G. Derumeaux: None. A. Berdeaux: None. B. Ghaleh: None.
- © 2014 by American Heart Association, Inc.