July 23, 2019Open Access
Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptation
Key Result
Transverse aortic constriction in 1-day-old mice induced a regenerative response with preserved cardiac function and cardiomyocyte proliferation, unlike maladaptive hypertrophy in 7-day-old mice.
Structured PICO
Does transverse aortic constriction at a regenerative stage (P1) prevent maladaptive cardiac remodeling compared to a non-regenerative stage (P7) in neonatal mice?
P
Population
Neonatal mice subjected to transverse aortic constriction at postnatal day 1 or day 7 to study cardiac regeneration and adaptation to pressure overload.
I
Intervention
Transverse aortic constriction (nTAC) at postnatal day 1 (regenerative stage)
C
Comparator
Transverse aortic constriction (nTAC) at postnatal day 7 (non-regenerative stage)
O
Outcome
Cardiac dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophysurrogate
Neonatal mice subjected to pressure overload during their regenerative window (P1) avoid maladaptive remodeling through GATA4-mediated cardiomyocyte proliferation and angiogenesis, offering a novel model for studying cardiac adaptation.
Limitations
- Did not demonstrate a causal link between enhanced myocardial nerve growth and the regenerative response during nTAC
- Animal model findings may not fully translate to human pathology
Abstract
Cardiac pressure overload (for example due to aortic stenosis) induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis in patients. In contrast to adult, 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 non-regenerative stage (at postnatal day 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 non-regenerative 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 non-regenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover novel potential therapeutic strategies.