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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/H257    most recent 00769.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huffman, L. C. Articles by Butler, K. L. Search for Related Content PubMed PubMed Citation Articles by Huffman, L. C. Articles by Butler, K. L.

Coronary effluent from a preconditioned heart activates the JAK-STAT pathway and induces cardioprotection in a donor heart

¹Department of Surgery and ²Institute of Molecular Pharmacology and Biophysics, University of Cincinnati, Cincinnati, Ohio

Submitted 3 July 2007 ; accepted in final form 1 November 2007

Preconditioning (PC) protects against ischemia-reperfusion (I/R) injury via the activation of the JAK-STAT pathway. We hypothesized that the mediators responsible for PC can be transferred to naive myocardium through the coronary effluent. Langendorff-perfused hearts from male Sprague-Dawley rats were randomized to paired donor/acceptor protocols with or without PC in the presence or absence of the JAK-2 inhibitor AG-490 (n = 6 for each group). Warmed, oxygenated coronary effluent collected during the reperfusion phases of PC (3 cycles of 5 min ischemia and 5 min reperfusion) was administered to acceptor hearts. The hearts were then subjected to 30 min ischemia and 40 min reperfusion. The left ventricles were analyzed for phosphorylated (p)STAT-1, pSTAT-3, Bax, Bcl, Bcl-X_L/Bcl-2-associated protein (BAD), and caspase-3 expression by Western blot. A separate group of hearts (n = 6) was analyzed for STAT activation immediately after the transfer of the PC effluent (no I-R). Baseline cardiodynamics were not different among the groups. End-reperfusion maximal change in pressure over time (+dP/dt_max) was significantly (P < 0.05) improved in acceptor PC (3,637 ± 199 mmHg/s) and donor PC (4,304 ± 347 mmHg/s) hearts over non-PC donor (2,020 ± 363 mmHg/s) and acceptor (2,624 ± 345 mmHg/s) hearts. Similar differences were seen for minimal change in pressure over time (–dP/dt_min). STAT-3 activation was significantly increased in donor and acceptor PC hearts compared with non-PC hearts. Conversely, pSTAT-1 and Bax expression was decreased in donor and acceptor PC hearts compared with non-PC hearts. No differences in Bcl, BAD, or caspase-3 expression were observed. Treatment with AG-490 attenuated the recovery of ±dP/dt in acceptor PC hearts and significantly reduced pSTAT-3 expression. The PC coronary effluent activates JAK-STAT signaling, limits apoptosis, and protects myocardial performance from I/R injury.

apoptosis; cardiac ischemia; ischemia-reperfusion injury; signal transducers and activators of transcription-3