摘要
Dysregulation of circadian rhythms associates with cardiovascular disorders.It is known that deletion of the core circadian gene Bma/1 in mice causes dilated car-diomyopathy.However,the biological rhythm regulation system in mouse is very different from that of humans.Whether BMAL1 plays a role in regulating human heart function remains unclear.Here we generated a BMAL1 knockout human embryonic stem cell(hESC)model and further derived human BMAL1 deficient cardiomy-ocytes.We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility,cal-cium dysregulation,and disorganized myofilaments.In addition,mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes,which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomy-ocyte function.We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression.BMAL1 knockout directly reduced BNIP3 protein level,causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function.Our data indicated that the core circadian gene S/VMLf is critical for normal mitochondria activities and cardiac function.Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.
基金
This work was supported by the National Natural Science Foundation of China(NSFC No.81322003,No.31571527,N.S.
No.31501098,Q.L.,No.81500241,C.X.,No.81870600,C.L.,No-81570771 and 31871189,RZ.Q.)
the Science and Technology Commission of Shanghai Municipality(No.17XD1400300,No.17JC1400200)
the National Key R&D Program of China 2018YFC2000202,and the Haiju program of National Children’s Medical Center EK1125180102.We apologize to people whose work was relevant to but not cited in this study due to limited space。
