title: Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target.
abstract: The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
authors.affiliation: FAHA Cardiovascular Research Center, University of Connecticut School of Medicine Farmington, Cardiovascular Research Institute, CT 06030-1110, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nagy
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shiroto
authors.forename: Gautam
authors.initials: G
authors.lastname: Malik
authors.forename: Chi-Kuang
authors.initials: CK
authors.lastname: Huang
authors.forename: Mathias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
authors.forename: Arpad
authors.initials: A
authors.lastname: Tosaki
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D017353:Gene Deletion; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D011494:Protein Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases