Abstract 16207: Rapamycin (Sirolimus®) Attenuates Myocardial Infarction and Cardiomyocyte Apoptosis following Ischemia-Reperfusion through JAK-STAT Signaling Pathway
Background: Rapamycin (Sirolimus®, RAPA) is used to prevent rejection of transplanted organs and coronary restenosis. We reported that RAPA induces protection against ischemia-reperfusion (I-R) injury in the heart through opening of mitochondrial KATP channels. Since STAT3 plays a role in modifying mitochondrial function, we hypothesized that activation of JAK-STAT3 pathway may play a critical role in RAPA-induced cardioprotection.
Methods and Results: Adult male ICR mice were pretreated with RAPA (0.25 mg/kg, i.p.) or vehicle (DMSO) with/without inhibitor of JAK2 (AG-490, 40 mg/kg, i.p.) or STAT3 (stattic, 20 mg/kg, i.p.). Thirty min later, the hearts were subjected to global ischemia (20 min) and reperfusion (30 min) in Langendorff mode (ex vivo) or in vivo regional ischemia by left coronary artery ligation (30 min) and reperfusion (24 hours). Infarct size was measured by computer morphometry of tetrazolium stained heart sections. RAPA reduced infarct size compared to vehicle (n=6–7/group; p<0.001, Fig 1A and B). RAPA-induced protection was abolished by AG-490 and stattic. Selective knock-down of STAT3 with lentiviral vector containing short hairpin RNA of STAT3 also attenuated RAPA-induced cardioprotection against regional I-R (Fig. 1C). Furthermore, RAPA-induced protection against necrosis and apoptosis in adult cardiomyocytes (subjected to simulated ischemia and reoxygenation) was also abolished by AG-490 and stattic. Western blots revealed that RAPA induced significant phosphorylation of STAT3 and glycogen synthesis 3-β in concert with increased expression of Bcl-2 and reduced levels of Bax in heart.
Conclusion: RAPA triggers a potent cardioprotective signaling involving JAK-STAT activation and downstream modulation of anti-apoptotic pathways. We propose that RAPA may be an important therapeutic modality to target STAT-3 activation for treatment of myocardial infarction following I-R injury in patients with cardiovascular disease.
- © 2010 by American Heart Association, Inc.