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

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 β1-Adrenergic receptor autoantibodies (β1-AA) could induce inhibition of myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether β1-AA induces cardiac autophagy rhythm disorder by affecting PER2 expression. This study find that β1-AA disrupts the autophagy rhythm in cardiomyocytes, primarily indicates by the decreased expression of the autophagy marker protein LC3; β1-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 β1-adrenergic receptor contributes to the reduction of Per2 protein caused by β1-AA. Knocking down Per2 with lentivirus reduces the inhibition of LC3 expression caused by β1-AA, while overexpressing Per2 in cardiomyocytes using lentivirus significantly restores β1-AA-induced decline in LC3 expression. At the same time, mTORC1 activation is found to participate in β1-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 β1-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.