Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes

SD Shapiro, AK Ranjan, Y Kawase… - Science translational …, 2014 - science.org
SD Shapiro, AK Ranjan, Y Kawase, RK Cheng, RJ Kara, R Bhattacharya
Science translational medicine, 2014science.org
Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac
repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2
gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-
based approach to occlude the left anterior descending artery in swine, which resulted in
substantial myocardial infarction. A week later, we performed left lateral thoracotomy and
injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into …
Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.
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