Involvement of Endothelin 1 in Remote Preconditioning-Induced Cardioprotection through connexin 43 and Akt/GSK-3β Signaling Pathway

Abstract

The present study was aimed to explore the role of endothelins in remote preconditioning (RP)-induced myocardial protection in ischemia-reperfusion (IR) injury. RP stimulus was given by subjecting hind limb to four cycles of ischemia and reperfuion (5 minutes each) using blood pressure cuff in male rats. Following RP, hearts were isolated and subjected to 30 minutes of ischemia and 120 minutes of reperfusion on Langendorff apparatus. The extent of myocardial injury was determined by measuring the levels of LDH-1, CK-MB and cardiac troponin T (cTnT) in coronary effluent; caspase-3 activity and Bcl 2 expression in heart (apoptosis); infarct size by triphenyl tetrazolium chloride and contractility parameters including left ventricular developed pressure, dp/dtmax dp/dtmin and heart rate. RP reduced ischemia reperfusion-induced myocardial injury, increased the levels of endothelin 1 (in blood), Akt-P, GSK-3β-P and P-connexin 43 (in hearts). Pretreatment with ETA receptor antagonist, BQ 123 (1 and 2 mg/kg), ETB receptor antagonist, BQ 788 (1 and 3 mg/kg) and dual inhibitor of ETA and ETB receptor, bonsentan (25 and 50 mg/kg) abolished these effects of RP. However, the effects of bonsentan were more pronounced in comparison to BQ 123 and BQ 788. It is concluded that RP stimulus may release endothelin 1 in the blood, which may activate myocardial ETA and ETB receptors to trigger cardioprotection through connexin 43 and Akt/GSK-3β pathway.

Tetramethylpyrazine exerts a protective effect against injury from acute myocardial ischemia by regulating the PI3K/Akt/GSK-3β signaling pathway

“…Experimental studies have indicated that intervention and ischemia preconditioning using some pharmacological agents can recruit the PI3K/Akt pathway and confer powerful cardioprotection [13]. It has been proposed that pharmacological targeting of the Akt pathway may potentially diminish ischemia reperfusion (IR) injury [14].…”

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway

“…The total protein content in the homogenate solution was measured by Lowery's method in which 100 µl of sample was mixed with 1 ml of color complex forming compound (sodium potassium tartrate, copper sulfate, Folin-Ciocalteau reagent) to yield a color, whose OD was measured at 750 nm. The apoptotic markers (bcl-2 and caspase 3) were represented with respect to total protein content [ 28 , 29 ].…”

The effect of an adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion

“…These results were later confirmed by Duda et al [ 93 ] . Recently, endogenous endothelin-1 and ET A receptor were found to be involved in the cardioprotective effect of remote preconditioning in rats [ 94 ] . However, there is little evidence that the selective ET A receptor antagonist BQ123 may increase cardiac tolerance to reperfusion in rabbits [ 95 ] .…”