Abstract 125: Genetic Deletion Of Telomerase Promotes Premature Cardiac Aging
Telomeropathies are a group of human diseases characterized by mutations in the telomerase gene, accelerated telomere attrition, and premature organ aging. Manifestations of telomere disease include bone marrow failure, liver cirrhosis, and lung fibrosis. It remains, however, to be documented whether loss of telomerase activity is coupled with alterations in cardiac structure and function. To address this issue, the heart of mice carrying a deletion of the RNA component of telomerase (Terc-/- mice) was studied at 3-13 months of age. This allowed us to define whether defects in telomerase function in cardiac stem cells (CSCs) and their progeny promote ventricular dysfunction independently from chronological age, which is typically associated with significant telomere erosion. For this purpose, the characteristics of the aging cardiomyopathy were defined first in 30-month-old wild-type mice (WT). Deteriorations in systolic and diastolic indices of myocardial contractility were detected in senescent mice by echo-Doppler, MRI, and invasive hemodynamics. Importantly, 6-month-old Terc-/- mice showed severe ventricular dysfunction comparable to that seen in 30 month-old WT. Telomere length in Terc-/- mouse CSCs was ~50% shorter than in age-matched WT cells but was comparable to that found in 30 month-old WT cells. The number of CSCs was 60% lower in Terc-/- than age-matched WT mice, and the fraction of BrdU-positive CSCs decreased 1.4-fold, from 25% to 14%. The absence of Terc led to a 50% reduction in myocyte turnover, which was coupled with myocyte hypertrophy and myocyte loss. BrdU labeling was reduced 60% in Terc-/- myocytes. Old CSCs formed a senescent progeny composed of cardiomyocytes, which carried markedly shortened telomeres and showed a severe depression in cell shortening and re-lengthening. Moreover, the renewal of endothelial cells was 75% lower in Terc-/- mice mimicking the rarefaction in capillary typically seen in the old myocardium. Our findings document that loss of telomerase activity is a critical determinant of cardiac aging with reduced cardiomyogenesis and vasculogenesis. These maladaptive responses may be operative in patients carrying mutations of telomerase.
- © 2013 by American Heart Association, Inc.