Cardiac pressure overload — for example, due to aortic stenosis — induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy, and interstitial fibrosis in patients. In contrast with adult mice, neonatal mice can efficiently regenerate the heart after injury in the first week after birth. To decipher whether insufficient cardiac regeneration contributes to the progression of pressure overload–dependent disease, we established a transverse aortic constriction protocol in neonatal mice (nTAC). nTAC in the nonregenerative stage (at P7) induced cardiac dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophy. In contrast, nTAC in the regenerative stage (at P1) largely prevented these maladaptive responses and was, in particular, associated with enhanced myocardial angiogenesis and increased cardiomyocyte proliferation, which both supported adaptation during nTAC. A comparative transcriptomic analysis between hearts after regenerative versus nonregenerative nTAC suggested the transcription factor GATA4 as master regulator of the regenerative gene program. Indeed, cardiomyocyte-specific deletion of GATA4 converted the regenerative nTAC into a nonregenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover potential therapeutic strategies.
Mona Malek Mohammadi, Aya Abouissa, Isyatul Azizah, Yinuo Xie, Julio Cordero, Amir Shirvani, Anna Gigina, Maren Engelhardt, Felix A. Trogisch, Robert Geffers, Gergana Dobreva, Johann Bauersachs, Joerg Heineke
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.