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Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection.

AbstractOBJECTIVE:
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.
METHODS AND 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.
AuthorsYajing Wang, Xiaoliang Wang, Jean-François Jasmin, Wayne Bond Lau, Rong Li, Yuexin Yuan, Wei Yi, Kurt Chuprun, Michael P Lisanti, Walter J Koch, Erhe Gao, Xin-Liang Ma
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 4 Pg. 934-42 (Apr 2012) ISSN: 1524-4636 [Electronic] United States
PMID22328772 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Adiponectin
  • Adipoq protein, mouse
  • Appl1 protein, mouse
  • Cadherins
  • Cav3 protein, mouse
  • Caveolin 3
  • Enzyme Activators
  • H-cadherin
  • Receptors, Adiponectin
  • adiponectin receptor 1, mouse
  • Cyclic AMP
  • AMP-Activated Protein Kinases
  • Adenylyl Cyclases
  • adenylyl cyclase 2
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Adaptor Proteins, Signal Transducing (metabolism)
  • Adenylyl Cyclases (metabolism)
  • Adiponectin (metabolism)
  • Animals
  • Apoptosis
  • Cadherins (metabolism)
  • Caveolin 3 (deficiency, genetics, metabolism)
  • Cyclic AMP (metabolism)
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Activators (pharmacology)
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Myocardial Infarction (genetics, metabolism, pathology, physiopathology, prevention & control)
  • Myocardial Reperfusion Injury (genetics, metabolism, pathology, physiopathology, prevention & control)
  • Myocardium (metabolism, pathology)
  • Protein Interaction Domains and Motifs
  • Receptors, Adiponectin (genetics, metabolism)
  • Signal Transduction (drug effects)
  • Time Factors
  • Transfection
  • Ventricular Function, Left

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