Gsk-3βInhibitors Mimic the Cardioprotection Mediated by Ischemic Pre- and Postconditioning in Hypertensive Rats

Luisa F González Arbeláez,Susana M Mosca,Ignacio A Pérez Núñez

doi:10.1155/2013/317456

Abstract

The aim of this study was to examine the effects of GSK-3β inhibitors compared with PRE and POS in spontaneously hypertensive rats (SHR). Isolated hearts were submitted to the following protocols: IC: 45 min global ischemia (GI) and 1-hour reperfusion (R); PRE: a cycle of 5 min GI and 10 minutes of R prior to 45 min GI; POS: three cycles of 30 sec GI/30 sec R at the start of R. Other hearts received lithium chloride (LiCl) or indirubin-3′-monoxime,5-iodo-(IMI) as GSK-3β inhibitors. All interventions reduced the infarct size observed in IC group. The expressions of P-GSK-3β and P-Akt decreased in IC and were restored after PRE, POS, and GSK-3β inhibitors treatments. An increase of cytosolic MnSOD activity and lipid peroxidation and a decrease of GSH content observed in IC hearts were attenuated in PRE, POS, and LiCl or IMI treatments. An increase of P-GSK-3β/VDAC physical association and a partial recovery of mitochondrial permeability were also detected after interventions. These data show that, in SHR hearts, GSK-3β inhibitors mimic the cardioprotection afforded by PRE and POS and suggest that a decrease in mitochondrial permeability mediated by P-GSK-3β/VDAC interaction is a crucial event.

Highlights

The left ventricular hypertrophy (LVH) consequent to chronically elevated blood pressure has been frequently associated with postischemic contractile dysfunction [1]
The treatment with LiCl or IMI before ischemia or at the beginning of reperfusion limited the infarct size at similar values to that obtained by PRE and POS
The present study demonstrates that the physical interaction of cytosolic P-GSK-3β with VDAC is involved in the cardioprotective effects of PRE and POS in isolated hearts from spontaneously hypertensive rats (SHR)

Summary

Introduction

The left ventricular hypertrophy (LVH) consequent to chronically elevated blood pressure has been frequently associated with postischemic contractile dysfunction [1] It has been previously shown in stroke-prone spontaneously hypertensive rats (SHR-SPs) [2, 3] and recently demonstrated by us in spontaneously hypertensive rats (SHR) [4] that LVH aggravates the irreversible reperfusion injury. The resulting inhibition of electron flow might explain the increased reactive oxygen species (ROS) formation induced by mPTP opening Since the latter event is favored by ROS [13], a vicious cycle of injury amplification is likely to be established, especially at the onset of reperfusion

Objectives

Results

Conclusion