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

Am J Physiol Heart Circ Physiol. 2008 Jan;294(1):H257-62. doi: 10.1152/ajpheart.00769.2007. Epub 2007 Nov 2.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3 / metabolism
  • Enzyme Activation
  • In Vitro Techniques
  • Ischemic Preconditioning, Myocardial*
  • Janus Kinases / metabolism*
  • Male
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Perfusion
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • STAT Transcription Factors / metabolism*
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction* / drug effects
  • Time Factors
  • Tyrphostins / pharmacology
  • Ventricular Pressure
  • bcl-2-Associated X Protein / metabolism
  • bcl-Associated Death Protein / metabolism
  • bcl-X Protein / metabolism


  • Bad protein, rat
  • Bax protein, rat
  • Bcl2l1 protein, rat
  • Protein Kinase Inhibitors
  • STAT Transcription Factors
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, rat
  • Stat3 protein, rat
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Janus Kinases
  • Casp3 protein, rat
  • Caspase 3