Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure
Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure
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DOI：
10.1161/01.res.0000093985.76901.af
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发表时间：
2003-10-03
影响因子：
20.1
通讯作者：
Anversa, P
中科院分区：
文献类型：
--
作者：
Chimenti, C;Kajstura, J;Anversa, P
时间性心肌老化被认为是时间对心脏功能储备的必然影响。老年患者的心力衰竭通常被解释为与衰老过程无关的叠加在老年心脏上的特发性或继发性肌病。因此，研究了老年患病心脏，以确定细胞再生是否与衰老死亡细胞的积累不成比例，从而导致心脏失代偿。对19例老年扩张型肌病患者的肌内膜活检标本与7例年龄相仿、心室功能正常的患者的标本进行了比较。10例原发性扩张型心肌病患者也进行了分析，以检测与老年病变心脏的差异。通过细胞周期抑制剂p16（INK4a）的表达和通过发夹1和2的细胞死亡来鉴定衰老细胞。通过MCM5标记、肌细胞有丝分裂指数和端粒酶功能评估原始细胞和肌细胞的复制。老年病心有中度肥大和扩张，p16（INK4a）阳性原始细胞和肌细胞的积累，没有结构损伤。细胞死亡显著增加，并且仅发生在具有显著端粒缩短的表达p16（INK4a）的细胞中。细胞增殖、有丝分裂指数和端粒酶增加，但不能补偿细胞死亡或阻止端粒缩短。特发性扩张型心肌病有严重的肥大和扩张，组织损伤，和最低水平的p16（INK4a）标记。总之，端粒侵蚀、细胞衰老和死亡是老年心脏病和心力衰竭的特征。
Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart. Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16(INK4a) and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16(INK4a) positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16(INK4a) that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16(INK4a) labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans.