Attenuation of apoptosis in vitro and ischemia/reperfusion injury in vivo in mouse skeletal muscle by P2Y6 receptor activation.
Activation of the G(q)-coupled P2Y(6) receptor heterologously expressed in astrocytes significantly attenuates apoptosis induced by tumor necrosis factor alpha (TNFalpha). We have extended the analysis of P2Y(6) receptor-induced cytoprotection to mouse skeletal muscle cells endogenously expressing this receptor. The endogenous P2Y(6) receptor agonist UDP and synthetic agonist MRS2693 protected C2C12 skeletal muscle cells against apoptosis in a concentration-dependent manner (0.1-10 nM) as determined by propidium iodide staining, histochemical analysis using hematoxylin and Hoechst 33258, and DNA fragmentation. The insurmountable P2Y(6) receptor antagonist MRS2578 blocked the protection. TNFalpha-induced apoptosis in C2C12 cells correlated with activation of the transcription factor NF-kappaB. The NF-kappaB activation was attenuated by 10nM MRS2693, which activated the antiapoptic ERK1/2 pathway. In an in vivo mouse hindlimb model, MRS2693 protected against skeletal muscle ischemia/reperfusion injury. The P2Y(6) receptor is a novel cytoprotective receptor that deserves further exploration in ameliorating skeletal muscle injury.
Mamedova
Liaman K
LK
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
Wang
Ruibo
R
Besada
Pedro
P
Liang
Bruce T
BT
Jacobson
Kenneth A
KA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D007150:Immunohistochemistry; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology; D020011:Protective Agents; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology*; D014530:Uridine Diphosphate / Q000494:pharmacology
D020011:Protective Agents; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate