P140Deficiency in Tissue Kallikrein abolishes the cardio protective effects of CsA during post-conditioning in mice

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Cardioprotective strategies, called postconditionning (PostC), that limit lethal reperfusion injury have a major clinical potential in acute myocardial infarction. Indeed, bolus injection of calcineurin inhibitor Cyclosporine A (CsA) at reperfusion reportedly reduces myocardial infarct size (IS) in mouse as well as in human. Bradykinin (BK) is equally protective in mouse and both molecules CsA and BK are able to modulate the opening of the mitochondrial Permeability Transition Pore (mPTP) to trigger their cardioprotection effects during ischemia-reperfusion (IR). We investigate for the first time whether in mouse BK is involved in the cardioprotection afforded against IR by CsA using Tissue Kallikrein deficient mice (TK-/-) lacking BK and their wild-type littermate (TK+/ + ).

Methods and Results

A branch of the left main coronary artery was reversibly ligated in mice to produce 30-min-ischemia followed by reperfusion (120 min), after which the degree of myocardial necrosis (IS as a percent of area at risk (AAR)) was assessed by measuring the AAR and IS. Two-year-old TK+/ + and TK-/- male mice were divided in two groups receiving 5 min before the reperfusion either the vehicule or 10 mg/kg of CsA. As expected, CsA (10mg/kg) reduced infarct size from IS/AAR= 35.4 ± 3.4 % of the ischemic zone in Ct-TK+/ + hearts to IS/AAR =13.6 ± 2.5% (p=0.001) in Csa-TK+/ + hearts. Interestingly, CsA is unable to reduce the Is in TK-/- mice (Ct-TK-/- IS/AAR= 31.8 ± 6.8%, vs CsA-TK-/- IS/AR= 29.8 ± 6.1%) suggesting that the protective effets of CsA are abolished in absence of the TK. Investigating the mitochondria functions, we demonstrated that TK presence does not impact on mitochondrial membrane potential or oxidative phosphorylation. However, we demonstrated that CsA treatment is able to inhibit the mPTP opening in TK+/ + mice while the CsA administration is unable to do so in TK-/- mice.


While still investigating the molecular mechanisms of CsA lack of efficacy in TK-/- mice, the present study demonstrate for the first time that null expression of TK abrogates the cardioprotective effects of a Pharmacological PostC afforded by a CsA bolus prior myocardial reperfusion in TK+/ + mice. Furthermore, we demonstrate that this loss of reactivity to CsA injection is due to mPTP loss of sensitivity to CsA.

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