Pathogenic remodeling following heart injury is due, in part, to the limited regenerative capacity of adult cardiomyocytes. Cell cycle induction has been recently explored as a therapeutic approach for heart failure, and to this end, expression of cyclin D2 in cardiomyocytes improves outcomes in mouse models follwoing myocardial infarction. In this episode, Gerd Hasenfuß, Loren Field, and Karl Toischer discuss their collaborative effort to further evaluate the effect of increased cyclin D2 on outcomes in response to other forms of heart failure. Cyclin D2 expression improved survival and cardiac function in mice exposed to pressure overload; however, cyclin D2-espressing mice were not protected from adverse effects in response to chronic volume overload. These results support further effort into the development of strategies to improve cardiomyocyte proliferation for some types cardiac injury.
Induction of the cell cycle is emerging as an intervention to treat heart failure. Here, we tested the hypothesis that enhanced cardiomyocyte renewal in transgenic mice expressing cyclin D2 would be beneficial during hemodynamic overload. We induced pressure overload by transthoracic aortic constriction (TAC) or volume overload by aortocaval shunt in cyclin D2–expressing and WT mice. Although cyclin D2 expression dramatically improved survival following TAC, it did not confer a survival advantage to mice following aortocaval shunt. Cardiac function decreased following TAC in WT mice, but was preserved in cyclin D2–expressing mice. On the other hand, cardiac structure and function were compromised in response to aortocaval shunt in both WT and cyclin D2–expressing mice. The preserved function and improved survival in cyclin D2–expressing mice after TAC was associated with an approximately 50% increase in cardiomyocyte number and exaggerated cardiac hypertrophy, as indicated by increased septum thickness. Aortocaval shunt did not further impact cardiomyocyte number in mice expressing cyclin D2. Following TAC, cyclin D2 expression attenuated cardiomyocyte hypertrophy, reduced cardiomyocyte apoptosis, fibrosis, calcium/calmodulin–dependent protein kinase IIδ phosphorylation, brain natriuretic peptide expression, and sustained capillarization. Thus, we show that cyclin D2–induced cardiomyocyte renewal reduced myocardial remodeling and dysfunction after pressure overload but not after volume overload.
Karl Toischer, Wuqiang Zhu, Mark Hünlich, Belal A. Mohamed, Sara Khadjeh, Sean P. Reuter, Katrin Schäfer, Deepak Ramanujam, Stefan Engelhardt, Loren J. Field, Gerd Hasenfuss