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This Article Full Text Full Text (PDF) All Versions of this Article: 291/2/H797    most recent 01334.2005v1 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 HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Butler, K. L. Articles by Gwathmey, J. K. Search for Related Content PubMed PubMed Citation Articles by Butler, K. L. Articles by Gwathmey, J. K.

STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium

Departments of ¹Surgery and ²Medicine, University of Cincinnati, Cincinnati, Ohio; and ³Harvard Medical School, Department of Medicine, and ⁴Gwathmey, Incorporated, Boston, Massachusetts

Submitted 19 December 2005 ; accepted in final form 9 March 2006

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 ± 58 vs. 1,028 ± 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt_max; 4,648 ± 309 vs. 2,737 ± 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum –dP/dt (–dP/dt_min; –2,239 ± 205 vs. –1,215 ± 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt_max (4,648 ± 309 vs. 3,241 ± 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and –dP/dt_min (–2,239 ± 205 vs. –1,323 ± 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.

ischemia-reperfusion; Janus-activated kinase; signal transducer and activator of transcription; cardiac preconditioning; myocardial hypertrophy

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