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Rapamycin (Sirolimus)–induced protection against ischemia‐reperfusion injury is mediated through AMPK, Akt and JAK/STAT pathways in mouse heart
Author(s) -
Das Anindita,
Salloum Fadi N,
Xi Lei,
Mayton Eric,
Desai Shivani K,
Ockaili Ramzi A,
Kukreja Rakesh C
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.601.6
Subject(s) - cardioprotection , ampk , protein kinase b , wortmannin , pharmacology , pi3k/akt/mtor pathway , phosphorylation , sirolimus , reperfusion injury , medicine , chemistry , jak stat signaling pathway , stat3 , ischemia , signal transduction , protein kinase a , biochemistry , receptor tyrosine kinase
Rapamycin (RAPA) is an approved drug to prevent rejection of transplanted organs and coronary restenosis. We reported that RAPA induces protection against ischemia‐reperfusion (I‐R) injury in the heart and cardiomyocytes. For determining a causative role of survival kinases (AMPK, Akt and JAK/STAT) in RAPA‐induced cardioprotection, adult male ICR mice were pretreated with RAPA (0.25 mg/kg, i.p.) or vehicle (DMSO). Hearts were isolated after 30 min and subjected to 20 min global I and 30 min R in Langendorff mode. RAPA significantly reduced infarct size as compared to DMSO (from 33.5±1.7% to 9.4±1.2%, n=7/group; p<0.001). This protection was abolished by AMPK inhibitor, compound c (20 mg/kg, i.p., 39.4±2.2%), PI3K inhibitor, wortmannin (15 μg/kg, i.p., 29.3±4.8%), JAK2 inhibitor, AG‐490 (40 mg/kg, i.p., 37.6±5.1%) and STAT3 inhibitor, stattic (20 mg/kg, i.p., 33.3±1.2%). Western blots revealed that RAPA induced phosphorylation of AMPK, Akt, STAT3 and GSK3β and enhanced the Bcl‐2/Bax ratio in the heart as compared to DMSO. These studies provide new evidence that activation of AMPK, Akt, JAK/STAT, and inactivation of GSK3β play critical role in RAPA‐induced protection against I‐R injury in the heart. (Supported by AHA BGIA 0765273U to AD and NIH HL51045, HL79424, HL93685 to RCK)