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Neonatal mice adopt to pressure overload by inducing cardiomyocyte proliferation and angiogenesis

ABSTRACT: Backgound: Cardiac pressure overload, for example in patients with aortic stenosis, induces irreversible damage in the myocardium leading to cardiac dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis. We therefore hypothesized that insufficient cardiac regeneration might contribute to the progression of pressure overload dependent disease. Here, we aimed to elucidate whether pressure overload in the regenerative stage shortly after birth could lead to a more adaptive cardiac response than in the non-regenerative stage in mice.nTAC in the non-regenerative stage induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, during induction of nTAC in the regenerative stage, cardiac function remained intact and this was associated with enhanced myocardial angiogenesis and innervation as well as increased cardiomyocyte proliferation, but neither hypertrophy nor fibrosis. Mechanistically, inhibition of cardiomyocyte proliferation and angiogenesis in nTAC in the regenerative phase by rapamycin triggered mortality and myocardial fibrosis, which both also similarly occurred upon inhibition of angiogenesis by PTK787, suggesting that both processes are essential for the adaptive cardiac response to nTAC. A comparative genome-wide transcriptomic analysis between hearts after nTAC in the regenerative versus the non-regenerative stage defined differentially expressed functional gene classes, and a related bioinformatics analysis 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.tablished a new model of neonatal pressure-overload in mice, which when applied in the regenerative postnatal stage, triggers a purely adaptive myocardial response. Employing this model to identify new regulators might lead to novel therapeutic strategies to combat pressure overload induced myocardial disease. Overall design: We established a transverse aortic constriction protocol in neonatal mice (nTAC) that could be induced either in the regenerative (at postnatal day P1) or in the non-regenerative stage (at P7) after birth. Echocardiography was used to assess cardiac dimensions and function in neonatal mice. Myocardial histological examinations were conducted to assess interstitial fibrosis, angiogenesis, innervation and cardiomyocyte proliferation. RNA deep sequencing was employed to compare the cardiac gene-expression pattern between nTAC in the regenerative versus the non-regenerative stage.

INSTRUMENT(S): Illumina HiSeq 2500 (Mus musculus)

ORGANISM(S): Mus musculus  

SUBMITTER: Joerg Heineke  

PROVIDER: GSE121308 | GEO | 2019-07-26


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Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation.

Malek Mohammadi Mona M   Abouissa Aya A   Azizah Isyatul I   Xie Yinuo Y   Cordero Julio J   Shirvani Amir A   Gigina Anna A   Engelhardt Maren M   Trogisch Felix A FA   Geffers Robert R   Dobreva Gergana G   Bauersachs Johann J   Heineke Joerg J  

JCI insight 20190723

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). nTA  ...[more]

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