Faculty Collaboration Database

Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther 2001 Feb;296(2):642-9

Date

02/13/2001

Pubmed ID

11160653

Scopus ID

2-s2.0-0035141233 (requires institutional sign-in at Scopus site)   138 Citations

Abstract

Stimulation of the delta(1)-opioid receptor has been shown to trigger ischemic preconditioning (IPC). Additionally, myocardial ischemia/reperfusion induces the activation of extracellular signal-regulated kinase (ERK). Therefore, we examined the role of ERK in acute cardioprotection induced by delta(1)-opioid receptor stimulation or IPC. Infarct size (IS) was expressed as a percentage of the area at risk (AAR). Control animals had an IS/AAR of 60.6 +/- 1.8. IPC and delta(1)-opioid receptor stimulation with TAN-67 reduced IS/AAR (8.2 +/- 1.3 and 30.2 +/- 2.4). Inhibition of ERK with the selective MEK-1 antagonist, PD 098059 during IPC or TAN-67 administration significantly reduced cardioprotection (41.5 +/- 6.4 and 63.0 +/- 4.8). Western Blot analysis and subsequent densitometry corroborated these observations. Control, TAN-67-, or IPC-treated hearts were harvested after 0, 5, 15, and 30 min of ischemia or 5, 30, and 60 min of reperfusion and separated into cytosolic and nuclear fractions. Both isoforms of ERK (p44 and p42) rapidly increased to greater levels throughout reperfusion in the nuclear fraction of IPC- and opioid-treated versus control rats, however, this increase was not attenuated by PD 098059. Conversely, the rapid activation of the 44-kDa isoform of ERK after 5 min of reperfusion in the cytosolic fraction was significantly increased in IPC- and opioid-treated hearts versus control, and this increase was abolished by pretreatment with PD 098059. Additionally, p42 was activated in the cytosolic fraction of IPC-treated animals. These results suggest a key role for the 44-kDa isoform of ERK in the cytoplasm during cardioprotection induced by either IPC or stimulation of the delta(1)-opioid receptor.

Author List

Fryer RM, Pratt PF, Hsu AK, Gross GJ

MESH terms used to index this publication - Major topics in bold

Analgesics, Opioid
Animals
Blood Pressure
Blotting, Western
COS Cells
Cell Nucleus
Cytosol
Enzyme Activation
Enzyme Inhibitors
Heart Diseases
Heart Rate
Ischemic Preconditioning, Myocardial
Isoenzymes
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Myocardial Infarction
Myocardial Reperfusion Injury
Rats
Rats, Wistar
Receptors, Opioid, delta
Receptors, Opioid, mu