Tissue kallikrein elicits cardioprotection by derect b2 receptor activation independent of kinin formation, Hypertension

Tissue kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that tissue kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of tissue kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek (BNK) rats after acute myocardial infarction (MI). Tissue kallikrein was injected locally into the myocardium of BNK rats after coronary artery ligation, with and without co-injection of icatibant (a kinin B2 receptor antagonist) and L-NAME (a nitric oxide synthase inhibitor). One day after MI, tissue kallikrein treatment significantly improved cardiac contractility, reduced myocardial infarct size and left ventricle-end-diastolic pressure in BNK rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/ macrophage accumulation in the ischemic myocardium in conjunction with increased nitric oxide (NO) levels and reduced myeloperoxidase activity. Icatibant and L-NAME abolished kallikrein’s effects, indicating a kinin B2 receptor-NO-mediated event. Moreover, inactive kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis or inflammatory cell infiltration after MI. In primary cardiomyocytes derived from BNK rats under serum-free conditions, active, but not inactive, kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/NO formation. This is the first study to demonstrate that tissue kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis and inflammation and improve cardiac performance of infarcted hearts