Postnatal Deletion of Bmal1 in Cardiomyocyte Promotes Pressure Overload Induced Cardiac Remodeling in Mice

Jun 22, 2022Journal of the American Heart Association

Removing Bmal1 in Heart Muscle Cells After Birth May Increase Heart Changes Caused by High Blood Pressure in Mice

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Abstract

Cardiomyocyte-specific deletion of Bmal1 leads to significantly increased cardiac hypertrophy and fibrosis in mouse models.

Mice with cardiomyocyte-specific deletion of Bmal1 exhibited enhanced cardiac hypertrophy and fibrosis after pressure overload.
RNA sequencing indicated significant activation of the PI3K/AKT signaling pathway in Bmal1 knockout mice.
In vitro studies demonstrated that loss of Bmal1 in cardiomyocytes increased hypertrophy and promoted fibroblast-to-myofibroblast differentiation.
Inhibition of AKT reversed the hypertrophic and fibrotic effects observed following Bmal1 knockdown.

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Background Mice with cardiomyocyte-specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin Ⅱ (AngⅡ) infusion. Methods and Results By generating a tamoxifen-inducible cardiomyocyte-specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or AngⅡ, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and AngⅡ induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA-sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine-induced cardiomyocyte hypertrophy and triggered fibroblast-to-myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro-hypertrophy and pro-fibrosis effects of Bmal1 knocking down. Conclusions These results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload-induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.

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Postnatal Deletion of Bmal1 in Cardiomyocyte Promotes Pressure Overload Induced Cardiac Remodeling in Mice

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