Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation.

Abstract

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 rats after acute myocardial infarction. Tissue kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, tissue kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester 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 myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek 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/nitric oxide 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.

• Authors: Julie Chao, Hang Yin, Lin Gao, Makoto Hagiwara, Bo Shen, Zhi-Rong Yang, Lee Chao
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 52 Issue 4 Pg. 715-20 (Oct 2008) ISSN: 1524-4563 [Electronic] United States
• PMID: 18768400 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptor, Bradykinin B2
• Serine Proteinase Inhibitors
• Nitric Oxide
• Aprotinin
• Peroxidase
• Tissue Kallikreins

Topics

• Animals
• Apoptosis
• Aprotinin (pharmacology)
• Cells, Cultured
• Disease Models, Animal
• Immunohistochemistry
• Male
• Myocardial Infarction (metabolism, pathology, physiopathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Nitric Oxide (metabolism)
• Peroxidase (metabolism)
• Rats
• Rats, Inbred BN
• Receptor, Bradykinin B2 (biosynthesis, drug effects)
• Serine Proteinase Inhibitors (pharmacology)
• Tissue Kallikreins (drug effects, metabolism)