SAPKs regulation of ischemic preconditioning

Area of Science:

• Cardiovascular physiology
• Molecular biology
• Biochemistry

Background:

• Stress-activated protein kinases (SAPKs), including c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase, are implicated in cellular responses to stress.
• Preconditioning (PC) is a phenomenon that confers protection against ischemia-reperfusion (I/R) injury in the heart, but the underlying molecular mechanisms are not fully elucidated.

Purpose of the Study:

• To investigate the role of SAPKs, specifically JNK and p38 MAP kinase, in the cardioprotective effects of preconditioning in isolated rat hearts.
• To determine if inhibiting or stimulating these kinases affects I/R injury and the protective mechanisms of PC.

Main Methods:

• Isolated rat hearts were subjected to a preconditioning protocol (four cycles of 5-min ischemia/10-min reperfusion) followed by a sustained I/R injury (30-min ischemia/2-h reperfusion).
• Hearts were pretreated with curcumin (JNK inhibitor), SB 203580 (p38 MAP kinase inhibitor), or anisomycin (JNK and p38 MAP kinase stimulator).
• Protein levels of JNK1, c-Jun, and p38 MAP kinase were assessed, and myocardial infarction size was measured.

Main Results:

• Ischemia-reperfusion (I/R) increased JNK1, c-Jun, and p38 MAP kinase levels. Preconditioning (PC) enhanced this induction, but subsequent I/R-mediated increases were blocked by PC.
• Curcumin inhibited JNK1 and c-Jun but not p38 MAP kinase. SB 203580 inhibited p38 MAP kinase but not JNK1 or c-Jun.
• Anisomycin, curcumin, and SB 203580 all reduced I/R-mediated myocardial infarction. However, curcumin or SB 203580 abolished the cardioprotective effects of PC.

Conclusions:

• Preconditioning-induced cardioprotection is mediated by a signal-transduction pathway involving both JNK1 and p38 MAP kinase.
• Transient activation of SAPKs is essential for the protective effects of preconditioning against ischemia-reperfusion injury.