Adenosine A(1) receptor mediates late preconditioning via activation of PKC-delta signaling pathway.
Protein kinase C (PKC) plays a central role in both early and late preconditioning (PC) but its association with inducible nitric oxide synthase (iNOS) is not clear in late PC. This study investigates the PKC signaling pathway in the late PC induced by activation of adenosine A(1) receptor (A(1)R) with adenosine agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) and the effect on iNOS upregulation. Adult male mice were pretreated with saline or CCPA (100 microg/kg iv) or CCPA (100 microg/kg iv) with PKC-delta inhibitor rottlerin (50 microg/kg ip). Twenty-four hours later, the hearts were isolated and perfused in the Langendorff mode. Hearts were subjected to 40 min of ischemia, followed by 30 min reperfusion. After ischemia, the left ventricular end-diastolic pressure (LVEDP) was significantly improved and the rate-pressure product (RPP) was significantly higher in the CCPA group compared with the ischemia-reperfusion (I/R) control group. Creatine kinase release and infarct size were significantly lower in the CCPA group compared with the I/R control group. These salutary effects of CCPA were abolished in hearts pretreated with rottlerin. Immunoblotting of PKC showed that PKC-delta was upregulated (150.0 +/- 11.4% of control group) whereas other PKC isoforms remained unchanged, and iNOS was also significantly increased (146.2 +/- 9.0%, P < 0.05 vs. control group) after 24 h of treatment with CCPA. The data show that PKC is an important component of PC with adenosine agonist. It is concluded that activation of A(1)R induces late PC via PKC-delta and iNOS signaling pathways.
Kudo
Mitsuhiro
M
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529, USA.
Wang
Yigang
Y
Xu
Meifeng
M
Ayub
Ahmar
A
Ashraf
Muhammad
M
D000098:Acetophenones / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C058394:2-chloro-N(6)cyclopentyladenosine; C085746:rottlerin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D003402:Creatine Kinase; D000241:Adenosine