Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation.
Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac myocyte proliferation, increased apoptosis and cardiac myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.
Leri
Annarosa
A
Department of Medicine, Cardiovascular Research Institute, New York Medical College, Valhalla, NY 10595, USA.
Franco
Sonia
S
Zacheo
Antonella
A
Barlucchi
Laura
L
Chimenti
Stefano
S
Limana
Federica
F
Nadal-Ginard
Bernardo
B
Kajstura
Jan
J
Anversa
Piero
P
Blasco
María A
MA
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016158:Genes, p53; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D019098:Telomerase