Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

Karl Toischer, Wuqiang Zhu, Mark Hünlich, Belal A. Mohamed, Sara Khadjeh, Sean P. Reuter, Katrin Schäfer, Deepak Ramanujam, Stefan Engelhardt, Loren Field, Gerd Hasenfuss

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4285-4296
Number of pages12
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
StatePublished - Dec 1 2017

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Cardiac Myocytes
Cyclins
Cyclin D2
Constriction
Pressure
Brain Natriuretic Peptide
Cardiomegaly
Protein Kinases
Hypertrophy
Transgenic Mice
Cell Cycle
Fibrosis
Heart Failure
Hemodynamics
Phosphorylation
Apoptosis
Calcium

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Toischer, K., Zhu, W., Hünlich, M., Mohamed, B. A., Khadjeh, S., Reuter, S. P., ... Hasenfuss, G. (2017). Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. Journal of Clinical Investigation, 127(12), 4285-4296. https://doi.org/10.1172/JCI81870

Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. / Toischer, Karl; Zhu, Wuqiang; Hünlich, Mark; Mohamed, Belal A.; Khadjeh, Sara; Reuter, Sean P.; Schäfer, Katrin; Ramanujam, Deepak; Engelhardt, Stefan; Field, Loren; Hasenfuss, Gerd.

In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4285-4296.

Research output: Contribution to journalArticle

Toischer, K, Zhu, W, Hünlich, M, Mohamed, BA, Khadjeh, S, Reuter, SP, Schäfer, K, Ramanujam, D, Engelhardt, S, Field, L & Hasenfuss, G 2017, 'Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload', Journal of Clinical Investigation, vol. 127, no. 12, pp. 4285-4296. https://doi.org/10.1172/JCI81870
Toischer K, Zhu W, Hünlich M, Mohamed BA, Khadjeh S, Reuter SP et al. Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. Journal of Clinical Investigation. 2017 Dec 1;127(12):4285-4296. https://doi.org/10.1172/JCI81870
Toischer, Karl ; Zhu, Wuqiang ; Hünlich, Mark ; Mohamed, Belal A. ; Khadjeh, Sara ; Reuter, Sean P. ; Schäfer, Katrin ; Ramanujam, Deepak ; Engelhardt, Stefan ; Field, Loren ; Hasenfuss, Gerd. / Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 12. pp. 4285-4296.
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