Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K

被引:37
作者
Cao, ZP
Liu, LJ
Van Winkle, DM
机构
[1] DVA Med Ctr, Anesthesiol Serv, Portland, OR 97239 USA
[2] DVA Med Ctr, Res Serv, Portland, OR 97239 USA
[3] Oregon Hlth & Sci Univ, Dept Anesthesiol, Portland, OR 97201 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2005年 / 288卷 / 04期
关键词
peptides; opioid; opioid receptor; ischemic preconditioning; signaling;
D O I
10.1152/ajpheart.00256.2004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K+ (K-ATP) channels. However, other elements of the Met(5)-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca2+-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 mu M) did not. Treatment with herbimycin (1 mu M) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr(992) and Tyr(1068). Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 mu M) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 mu M), and chelerythrine (2 mu M). The PI3K inhibitor LY-294002 (20 mu M) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser(473) was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.
引用
收藏
页码:H1955 / H1964
页数:10
相关论文
共 51 条
[1]   EFFECTS OF 2,3-BUTANEDIONE MONOXIME (BDM) ON CONTRACTURE AND INJURY OF ISOLATED RAT MYOCYTES FOLLOWING METABOLIC INHIBITION AND ISCHEMIA [J].
ARMSTRONG, SC ;
GANOTE, CE .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1991, 23 (09) :1001-1014
[2]   Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway [J].
Brunet, A ;
Datta, SR ;
Greenberg, ME .
CURRENT OPINION IN NEUROBIOLOGY, 2001, 11 (03) :297-305
[3]   Agonist activation of p42 and p44 mitogen-activated protein kinases following expression of the mouse delta opioid receptor in Rat-1 fibroblasts: Effects of receptor expression levels and comparisons with G-protein activation [J].
Burt, AR ;
Carr, IC ;
Mullaney, I ;
Anderson, NG ;
Milligan, G .
BIOCHEMICAL JOURNAL, 1996, 320 :227-235
[4]   Activation of δ- and κ-opioid receptors by opioid peptides protects cardiomyocytes via KATP channels [J].
Cao, ZP ;
Liu, LJ ;
Van Winkle, DM .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2003, 285 (03) :H1032-H1039
[5]   Naloxone blockade of myocardial ischemic preconditioning does not require central nervous system participation [J].
Chien, GL ;
Mohtadi, K ;
Wolff, RA ;
Van Winkle, DM .
BASIC RESEARCH IN CARDIOLOGY, 1999, 94 (02) :136-143
[6]   Naloxone blockade of myocardial ischemic preconditioning is stereoselective [J].
Chien, GL ;
VanWinkle, DM .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1996, 28 (09) :1895-1900
[7]   Cellular survival: a play in three Akts [J].
Datta, SR ;
Brunet, A ;
Greenberg, ME .
GENES & DEVELOPMENT, 1999, 13 (22) :2905-2927
[8]   Signal characteristics of G protein-transactivated EGF receptor [J].
Daub, H ;
Wallasch, C ;
Lankenau, A ;
Herrlich, A ;
Ullrich, A .
EMBO JOURNAL, 1997, 16 (23) :7032-7044
[9]   Specificity and mechanism of action of some commonly used protein kinase inhibitors [J].
Davies, SP ;
Reddy, H ;
Caivano, M ;
Cohen, P .
BIOCHEMICAL JOURNAL, 2000, 351 (351) :95-105
[10]   Role of nitric oxide in myocardial preconditioning [J].
Dawn, B ;
Bolli, R .
NITRIC OXIDE: NOVEL ACTIONS, DELETERIOUS EFFECTS AND CLINICAL POTENTIAL, 2002, 962 :18-41