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.

[Hypertension-induced fibrosis: a balance story]. / La fibrose dans l'hypertension artérielle : une histoire d'équilibre.

Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results in cardiac transcriptomic changes induced by mechanical and hormonal factors (angiotensin II and aldosterone are the most important). The major features of cardiac remodeling are the hypertrophy of cardiomyocytes, interstitial and perivascular fibrosis, and microvascular rarefaction. Inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS) participates to the development of heart failure. The respective roles of angiotensin II and aldosterone in cardiac remodeling are poorly understood. The development of fibrosis in the heart depends of a balance between profibrotic (TGFß, CTGF, inflammation) and antifibrotic (BNP, ANP, BMP4 and BMP7) factors. The profibrotic and proinflammatory effects of angiotensin II and aldosterone are very well demonstrated; however, their actions on antifibrotic factors expression are unknown. In order to explore this, we used RenTgKC mice overexpressing renin into the liver, leading to an increased plasma angiotensin II and thus induction of severe hypertension, and AS mice overexpressing aldosterone synthase (AS) in cardiomyocytes which have a doubled intracardiac aldosterone concentration. Male AS mice have a dysfunction of the coronary arteries relaxation without structural and functional changes of the myocardium. Mice derived from a crossing between the RenTgKC and AS strains were used in this work. It is shown that angiotensin II induces the expression of BNP and BMPs which ultimately slows the progression of myocardial fibrosis, and that aldosterone inhibits the expression of these factors and thus worsens the fibrosis.