Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia.
Tissue kallikrein (TK), a major kinin-forming enzyme, is synthesized in the heart and arteries. We tested the hypothesis that TK plays a protective role in myocardial ischemia by performing ischemia-reperfusion (IR) injury, with and without ischemic preconditioning (IPC) or ACE inhibitor (ramiprilat) pretreatment, in vivo in littermate wild-type (WT) or TK-deficient (TK-/-) mice. IR induced similar infarcts in WT and TK-/-. IPC reduced infarct size by 65% in WT, and by 40% in TK-/- (P<0.05, TK-/- vs WT). Ramiprilat also reduced infarct size by 29% in WT, but in TK-/- its effect was completely suppressed. Pretreatment of WT with a B2, but not a B1, kinin receptor antagonist reproduced the effects of TK deficiency. However, B2 receptor-deficient mice (B2-/-) unexpectedly responded to IPC or ramiprilat like WT mice. But pretreatment of the B2-/- mice with a B1 antagonist suppressed the cardioprotective effects of IPC and ramiprilat. In B2-/-, B1 receptor gene expression was constitutively high. In WT and TK-/- mice, both B2 and B1 mRNA levels increased several fold during IR, and even more during IPC+IR. Thus TK and the B2 receptor play a critical role in the cardioprotection afforded by two experimental maneuvers of potential clinical relevance, IPC and ACE inhibition, during ischemia.
Griol-Charhbili
V
V
INSERM U652/367, Paris, France.
Messadi-Laribi
E
E
Bascands
J L
JL
Heudes
D
D
Meneton
P
P
Giudicelli
J F
JF
Alhenc-Gelas
F
F
Richer
C
C
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000502:physiology; D020840:Tissue Kallikreins / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C052549:ramiprilat; D020840:Tissue Kallikreins; D017257:Ramipril