Published online before print October 4, 2001, doi: 10.1161/hh2201.099452
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Submitted on August 6, 2001
Revised on September 20, 2001
Accepted on September 20, 2001
p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart. Involvement of NF-
B and iNOS
From the Division of Cardiology, Departments of Medicine (T.C.Z., R.C.K.), Surgery (M.M.T.), and Radiation Oncology (K.C.V.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Va.
* To whom correspondence should be addressed. E-mail: rakesh{at}hsc.vcu.edu.
We investigated the role of stress-activated p38 MAP kinase (p38/SAPK-2) signaling in delayed preconditioning of the heart. Adult male out-bred ICR mice were treated with p38 activator, anisomycin (0.1 mg/kg IP), or vehicle (5% DMSO). Twenty-four hours later, hearts were perfused in Langendorff mode and subjected to 30 minutes of ischemia and 30 minutes of reperfusion. Improvement in postischemic recovery of end-diastolic pressure and reduction in infarct size was observed, which was abolished by SB203580, a specific p38 inhibitor, and pyrrolidinediethyldithiocarbamate (PDTC), the NF-B inhibitor, but not by PD 98059, a specific inhibitor for MEK1 or 2. Transient increase in p38 phosphorylation was observed 15 minutes after anisomycin treatment which subsided by 30 minutes. Electrophoretic mobility shift assay demonstrated rapid activation of NF-B DNA binding with anisomycin, peaking at 30 minutes. Western blot confirmed the accumulation of p50 and p65 in nuclear extracts after anisomycin treatment. Anisomycin-induced NF-B DNA binding activity was inhibited by SB203580 and PDTC. Expression of inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) synthesis were enhanced in anisomycin-treated mice. SB203580 and PDTC blocked the increased expression of iNOS and increase in synthesis of NO. Selective iNOS inhibitor S-methylisothiourea abolished the protective effect of anisomycin. Furthermore, postischemic cardioprotective effect of anisomycin was absent in mice with targeted ablation of iNOS gene but not in the wild-type B6.129 mice. For the first time, these results suggest that direct pharmacological activation of p38 triggers delayed preconditioning by signaling mechanism involving NF-B activation and synthesis of NO from iNOS.
Key words: anisomycin • p38 MAP kinase • NF-
B •
iNOS •
nitric oxide •
ischemia
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