Reduced expression of the PER2 protein contributes to β (1)-AA-induced cardiac autophagy rhythm disorders.

Heart failure may be linked to fluctuations in the rhythm of autophagy in cardiomyocytes throughout the day. Circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research confirmed that the presence of β (1)-adrenergic receptor autoantibodies (β (1)-AAs) could inhibit myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether β (1)-AA induces cardiac autophagy rhythm disorders by affecting PER2 expression. In this study, we find that β (1)-AA disrupts the autophagy rhythm in cardiomyocytes, which is primarily indicated by decreased expression of the autophagy marker protein LC3. β (1)-AA disrupts the rhythmic expression of the PER2 protein in myocardial cells, which is manifested mainly by a decrease in PER2 protein expression. Metoprolol is used to verify that the β (1)-adrenergic receptor contributes to the reduction in the Per2 protein caused by β (1)-AA. Knockdown of Per2 with lentivirus reduces the inhibition of LC3 expression caused by β (1)-AA, whereas overexpression of Per2 in cardiomyocytes using lentivirus significantly restores the β (1)-AA-induced decrease in LC3 expression. Moreover, mTORC1 activation is found to participate in β (1)-AA-induced autophagy inhibition in cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, the decreased expression of the PER2 protein caused by β (1)-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides an experimental basis for the precise treatment of cardiovascular diseases from the perspective of biological rhythm.