TY - JOUR
T1 - Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes
AU - Shapiro, Scott D.
AU - Ranjan, Amaresh K.
AU - Kawase, Yoshiaki
AU - Cheng, Richard K.
AU - Kara, Rina J.
AU - Bhattacharya, Romit
AU - Guzman-Martinez, Gabriela
AU - Sanz, Javier
AU - Garcia, Mario J.
AU - Chaudhry, Hina W.
PY - 2014/2/19
Y1 - 2014/2/19
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.3007668
DO - 10.1126/scitranslmed.3007668
M3 - Article
C2 - 24553388
AN - SCOPUS:84896381748
SN - 1946-6234
VL - 6
JO - Science translational medicine
JF - Science translational medicine
IS - 224
M1 - 224ra27
ER -