Research Article: Age-Dependent Oxidative DNA Damage Does Not Correlate with Reduced Proliferation of Cardiomyocytes in Humans

Date Published: January 18, 2017

Publisher: Public Library of Science

Author(s): Yanhui Huang, Haifa Hong, Minghui Li, Jinfen Liu, Chuan Jiang, Haibo Zhang, Lincai Ye, Jinghao Zheng, Katherine Yutzey.


Postnatal human cardiomyocyte proliferation declines rapidly with age, which has been suggested to be correlated with increases in oxidative DNA damage in mice and plays an important role in regulating cardiomyocyte proliferation. However, the relationship between oxidative DNA damage and age in humans is unclear.

Sixty right ventricular outflow myocardial tissue specimens were obtained from ventricular septal defect infant patients during routine congenital cardiac surgery. These specimens were divided into three groups based on age: group A (age 0–6 months), group B (age, 7–12 months), and group C (>12 months). Each tissue specimen was subjected to DNA extraction, RNA extraction, and immunofluorescence.

Immunofluorescence and qRT-PCR analysis revealed that DNA damage markers—mitochondrial DNA copy number, oxoguanine 8, and phosphorylated ataxia telangiectasia mutated—were highest in Group B. However immunofluorescence and qRT-PCR demonstrated that two cell proliferation markers, Ki67 and cyclin D2, were decreased with age. In addition, wheat germ agglutinin-staining indicated that the average size of cardiomyocytes increased with age.

Oxidative DNA damage of cardiomyocytes was not correlated positively with age in human beings. Oxidative DNA damage is unable to fully explain the reduced proliferation of human cardiomyocytes.

Partial Text

Cardiomyocyte deficiency underlies most causes of heart failure, which is the most common cause of disease-related deaths among citizens within industrialized nations [1]. Cardiomyocyte deficiency is mostly due to limited amounts of proliferating cardiomyocytes, which are not sufficient for ameliorating contractile dysfunction [2]. Thus, there is a profound demand to replenish the cardiomyocytes that are lost during heart failure by either promoting the proliferation of endogenous cardiomyocytes or facilitating stem cell differentiation (3,4)[3,4]. The percentage of proliferating cardiomyocytes in mammals declines with age, especially past the neonatal period, during which both humans and rodents have more proliferating cardiomyocytes than in any other period [5, 6]. The mechanism that underlies this reduced proliferation of cardiomyocytes remains unknown.

Cardiomyocyte proliferation contributes to postnatal heart growth in young humans and is very important in recovering heart function [16]. However mammalian cardiomyocytes lose proliferation activities during the aging process and cycling cardiomyocytes are almost undetectable by adulthood [16]. These limited numbers of cycling cardiomyocytes renders heart regeneration and functional recovery to be nearly impossible in adults, especially as the underling mechanism for the loss of mammalian cardiomyocyte proliferation remains to be elucidated. Currently, there are two possible explanations for this phenomenon: 1) The well-organized contractile architecture of adult cardiomyocytes may physically encumber cell division [2] and 2) Cardiomyocyte centrosomal integrity is lost shortly after birth, which contributes to a post-mitotic state of mammalian cardiomyocytes [19], as DNA integrity is a critical factor that impacts cell cycle activity [7,9]. However, these studies were performed using animal models and there are currently no data obtained from human studies. This study is the first report to investigate the relationship between DNA integrity and cardiomyocyte proliferation in humans.




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