Abstract 18300: Myocardial Ischemia Induces Telomerase Activity in the Mouse Heart

Abstract

Introduction: The incidence of cardiovascular disease rises with age. Ischemia and oxidative stress-induced DNA damage and telomere erosion may accelerate cardiac senescence. The enzyme telomerase has been shown to protect cardiovascular cells from mitochondrial oxidative stress independent of telomere elongation. We examined whether myocardial ischemia impacts on telomere biology and cellular aging in the infarcted mouse heart. Methods and results: C57Bl/6 mice (10 weeks old, n=6-8 per group) were subjected to anterior myocardial ischemia induced by proximal ligation of the left anterior descendant coronary artery or sham operation. Cardiac MRI was used to verify infarct localization and measure LV function, showing that ejection fraction was reduced in MI mice (47±5% vs. 68±3% in sham, p<0.01). Sham and MI mice were compared 3 days, 7 days, or 4 weeks after LAD ligation and myocardial infarct zone (IZ) and remote zone (RZ) were analyzed. Telomerase activity as measured by TRAP assays was elevated in the infarct zone 3 days after LAD ligation (187±9% vs. sham mice, p<0.01), but not in the remote zone (113±35%). Seven days after myocardial infarction, telomerase was up-regulated both, in the infarct zone (177±31%) and the remote zone (154±26%). This effect was even more pronounced 4 weeks after LAD ligation (IZ: 271±14%; RZ 223±28%). In concert with telomerase activation, telomere repeat binding factor (TRF) 2 protein expression was up-regulated in the infarct zone after three days (337±25%) and in both areas after 7 days (IZ: 431±48%; RZ: 380±31%) and less strongly after 4 weeks (IZ: 170±23%; RZ: 141±27%). In parallel to telomerase activity and TRF2 expression, the apoptosis and senescence markers p53 (189±11%), Chk2 (167±32%), bax/bcl2-ratio (278±27%) and p16 (518±42%) were up-regulated in the myocardium of MI mice after 4 weeks (all shown values p<0.05 vs. myocardial tissue of sham-operated mice). Conclusion: Myocardial telomerase and telomere-associated factors are up-regulated in a time- and region-specific manner in the infarcted mouse heart in concert with apoptosis and cell-cycle regulators. This regulatory process may be of relevance for myocardial survival, inflammation, and remodelling after ischemia.