Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury.
OBJECTIVE
Emerging evidence indicates that nuclear receptors play a critical regulatory role in cardiovascular physiology/pathology. Recently, farnesoid-X-receptor (FXR), a member of the metabolic nuclear receptor superfamily, has been demonstrated to be expressed in vascular cells, with important roles in vascular physiology/pathology. However, the potential cardiac function of FXR remains unclear. We investigated the cardiac expression and biological function of FXR.


RESULTS
Farnesoid-X-receptor was detected in both isolated neonatal rat cardiac myocytes and fibroblasts. Natural and synthetic FXR agonists upregulated cardiac FXR expression, stimulated myocyte apoptosis, and reduced myocyte viability dose- and time-dependently. Mechanistic studies demonstrated that FXR agonists disrupted mitochondria, characterized by mitochondrial permeability transition pores activation, mitochondrial potential dissipation, cytochrome c release, and both caspase-9 and -3 activation. Such mitochondrial apoptotic responses were abolished by siRNA-mediated silencing of endogenous FXR or pharmacological inhibition of mitochondrial death signalling. Furthermore, low levels of FXR were detected in the adult mouse heart, with significant (∼2.0-fold) upregulation after myocardial ischaemia/reperfusion (MI/R). Pharmacological inhibition or genetic ablation of FXR significantly reduced myocardial apoptosis by 29.0-53.4%, decreased infarct size by 23.4-49.7%, and improved cardiac function in ischaemic/reperfused myocardium.


CONCLUSIONS
These results demonstrate that nuclear receptor FXR acts as a novel functional receptor in cardiac tissue, regulates apoptosis in cardiomyocytes, and contributes to MI/R injury.
Department of Cardiology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Jun
J
Pu
Ancai
A
Yuan
Peiren
P
Shan
Erhe
E
Gao
Xiaoliang
X
Wang
Yajing
Y
Wang
Wayne Bond
WB
Lau
Walter
W
Koch
Xin-Liang
XL
Ma
Ben
B
He
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011282:Pregnenediones / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D053148:Caspase 3; D053453:Caspase 9; D002635:Chenodeoxycholic Acid; D016572:Cyclosporine; D045304:Cytochromes c; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D011282:Pregnenediones; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D051028:bcl-2-Associated X Protein; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione; C412815:GW 4064