Tissue kallikrein is required for the cardioprotective effect of cyclosporin A in myocardial ischemia in the mouse.

Clinical and experimental studies suggest that pharmacological postconditioning with Cyclosporin A (CsA) reduces infarct size in cardiac ischemia and reperfusion. CsA interacts with Cyclophilin D (CypD) preventing opening of the mitochondrial permeability transition pore (mPTP). Tissue kallikrein (TK) and its products kinins are involved in cardioprotection in ischemia. CypD knockout mice are resistant to the cardioprotective effects of both CsA and kinins suggesting common mechanisms of action. Using TK gene knockout mice, we investigated whether the kallikrein-kinin system is involved in the cardioprotective effect of CsA. Homozygote and heterozygote TK deficient mice (TK(-/-), TK(+/-)) and wild type littermates (TK(+/+)) were subjected to cardiac ischemia-reperfusion with and without CsA postconditioning. CsA reduced infarct size in TK(+/+) mice but had no effect in TK(+/-) and TK(-/-) mice. Cardiac mitochondria isolated from TK(-/-) mice had indistinguishable basal oxidative phosphorylation and calcium retention capacity compared to TK(+/+) mice but were resistant to CsA inhibition of mPTP opening. TK activity was documented in mouse heart and rat cardiomyoblasts mitochondria. By proximity ligation assay TK was found in close proximity to the mitochondrial membrane proteins VDAC and Tom22, and CypD. Thus, partial or total deficiency in TK induces resistance to the infarct size reducing effect of CsA in cardiac ischemia in mice, suggesting that TK level is a critical factor for cardioprotection by CsA. TK is required for the mitochondrial action of CsA and may interact with CypD. Genetic variability in TK activity has been documented in man and may influence the cardioprotective effect of CsA.

[The endothelin system: its involvement in the cardiovascular system]. / Le système endothéline : son implication dans le système cardiovasculaire.

The endothelin (ET)-system is composed of three endothelins, two receptors and two enzymes. The study of this system presents a great interest to understand the cardiovascular physiopathology. The ET-system is involved in cardiac organogenesis, angiogenesis and vascular tone homeostasis. Its role in arterial pulmonary hypertension, arterial hypertension and atherosclerosis has been shown. The numerous ET-system's targets suggest that it could be involved in pathologies which bring together various cardiovascular disorders such as the obstructive sleep apnoea syndrome. Thus, the ET-system generates today a lively interest for experimental and clinical trials.

[Hypoxic preconditioning: role of transcription factor HIF-1alpha]. / Préconditionnement hypoxique: rôle du facteur de transcription HIF-1alpha.

The delayed form of myocardial preconditioning is of particular interest because of its large window of protection. It involves many signalisation pathways who, along with transcription factors, activate cardioprotective genes. Amongst the latter, the hypoxia inducible factor 1 (HIF-1) whose a subunit is stabilized by hypoxia, appears to play a pivotal role in the delayed preconditioning induced by hypoxia. The stabilisation of HIF-1alpha by inhibitors of prolyl-4-hydroxylases, the enzymes responsible for its degradation in normoxia, reproduces the cardioprotective effects of hypoxia. These enzymes represent promising therapeutic targets for the treatment of various cardiovascular diseases.

Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart.

Administration of recombinant human erythropoietin (rhEPO) is known to induce protection against cardiac ischaemia injury improving functional recovery and reducing apoptosis. But the underlying mechanisms are not elucidated. We determined the role of nitric oxide synthases (NOS) as well as ATP-dependent (K(ATP)) and calcium-activated (K(Ca)) potassium channels in the early cardioprotection induced by rhEPO. Wistar male rats were divided into two experimental groups treated by rhEPO (5,000 IU/kg, i.p.) or saline (control group). One hour later, rats were anaesthetized, hearts isolated, retrogradely perfused and submitted to a 30-min no-flow global ischaemia followed by 120 min of reperfusion sequence. Cardiac functional recovery (left ventricular developed pressure, LVDP) was significantly higher in the group treated by rhEPO (LVDP at 30 min reperfusion: 71.7 +/- 2.3 mmHg) compared with the control group (57.4 +/- 5.8 mmHg). We observed the same significant effect on its derivative (dP/dt). The rhEPO-induced improvement in ventricular function was abolished by perfusion prior to ischaemia with either N-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) or N-(3-(aminomethyl)benzyl)acetamidine (1,400W, a specific inducible NOS inhibitor) or 5-hydroxydecanoic acid (5HD, a mitochondrial K(ATP) channel blocker) but not with paxilline (a K(Ca) channel inhibitor). Thus, in vivo rhEPO administration provides early preconditioning against ischaemic injury in the isolated perfused rat heart that is dependent on iNOS and mitochondrial K(ATP) channels.