Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection.
OBJECTIVE
Adiponectin (APN) system malfunction is causatively related to increased cardiovascular morbidity/mortality in diabetic patients. The aim of the current study was to investigate molecular mechanisms responsible for APN transmembrane signaling and cardioprotection.


RESULTS
Compared with wild-type mice, caveolin-3 knockout (Cav-3KO) mice exhibited modestly increased myocardial ischemia/reperfusion injury (increased infarct size, apoptosis, and poorer cardiac function recovery; P<0.05). Although the expression level of key APN signaling molecules was normal in Cav-3KO, the cardioprotective effects of APN observed in wild-type were either markedly reduced or completely lost in Cav-3KO. Molecular and cellular experiments revealed that APN receptor 1 (AdipoR1) colocalized with Cav-3, forming AdipoR1/Cav-3 complex via specific Cav-3 scaffolding domain binding motifs. AdipoR1/Cav-3 interaction was required for APN-initiated AMP-activated protein kinase (AMPK)-dependent and AMPK-independent intracellular cardioprotective signalings. More importantly, APPL1 and adenylate cyclase, 2 immediately downstream molecules required for AMPK-dependent and AMPK-independent signaling, respectively, formed a protein complex with AdipoR1 in a Cav-3 dependent fashion. Finally, pharmacological activation of both AMPK plus protein kinase A significantly reduced myocardial infarct size and improved cardiac function in Cav-3KO animals.


CONCLUSIONS
Taken together, these results demonstrated for the first time that Cav-3 plays an essential role in APN transmembrane signaling and APN anti-ischemic/cardioprotective actions.
Department of Physiology, Shanxi Medical University, Taiyuan, China.
Yajing
Y
Wang
Xiaoliang
X
Wang
Jean-François
JF
Jasmin
Wayne Bond
WB
Lau
Rong
R
Li
Yuexin
Y
Yuan
Wei
W
Yi
Kurt
K
Chuprun
Michael P
MP
Lisanti
Walter J
WJ
Koch
Erhe
E
Gao
Xin-Liang
XL
Ma
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D051244:Caveolin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left
D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C499919:Adipoq protein, mouse; C510733:Appl1 protein, mouse; D015820:Cadherins; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D020536:Enzyme Activators; C099972:H-cadherin; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; D000242:Cyclic AMP; D055372:AMP-Activated Protein Kinases; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2