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bioRxiv · 10.1101/2024.12.06.627296

Reduced expression of PER2 protein contrbutes to β1-AA induced cardiac autophagy rhythm disorder

Li, P.·feng, J.·Guo, J.·Xue, J.·Li, Y.·Wen, S.·Wang, X.·Liu, H.·Wang, l.
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Abstract

It has been confirmed that heart failure may be linked to fluctuations in autophagy rhythm of cardiomyocytes throughout the day. It is known that circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research has confirmed the presence of {beta}1-Adrenergic receptor autoantibodies ({beta}1-AA) could induce inhibition of myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether {beta}1-AA induces cardiac autophagy rhythm disorder by affecting PER2 expression. This study find that {beta}1-AA disrupts the autophagy rhythm in cardiomyocytes, primarily indicates by the decreased expression of the autophagy marker protein LC3; {beta}1-AA induces disruption of the rhythmic expression of PER2 protein in myocardial cells, mainly manifests by a decrease in PER2 protein expression; Metoprolol is employed to verify that the {beta}1-adrenergic receptor contributes to the reduction of Per2 protein caused by {beta}1-AA. Knocking down Per2 with lentivirus reduces the inhibition of LC3 expression caused by {beta}1-AA, while overexpressing Per2 in cardiomyocytes using lentivirus significantly restores {beta}1-AA-induced decline in LC3 expression. At the same time, mTORC1 activation is found to participate in {beta}1-AA-induced autophagy inhibition of cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, it is confirmed that the decreased expression of PER2 protein caused by {beta}1-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides experimental basis for the precision treatment of cardiovascular diseases from the perspective of biological rhythm.

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Li, P., feng, J., Guo, J., Xue, J., Li, Y., Wen, S., Wang, X., Liu, H., Wang, l.. 2024-12-07. Reduced expression of PER2 protein contrbutes to β1-AA induced cardiac autophagy rhythm disorder. https://doi.org/10.1101/2024.12.06.627296

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