Modulation of hypotensive effects of kinins by cathepsin K.
Kinins are pro-inflammatory peptides, which participate in the maintenance of cardiovascular homeostasis, and play a key role in numerous diseases, including lung fibrosis and hypertension. Evidence has been provided recently for the presence of alternative mechanisms of bradykinin generation and/or degradation. Here we showed that cathepsin K may act as a potent kinin-degrading enzyme in bloodstream. Contrary to cathepsin L, cathepsin K attenuates kallikrein-induced decrease of rat blood pressure, and reduces the hypotensive effect of bradykinin in a dose-dependent manner. Moreover, we identified, by engineering the S2 subsite of both recombinant enzymes, two critical residues involved respectively in the kininase activity of cathepsin K, i.e. Tyr67/Leu205, versus kininogenase activity of cathepsin L, i.e. Leu67/Ala205. In conclusion, according to its ability to modulate hypotensive effects of kinins, we propose that cathepsin K is a kininase of biological relevance, in complement of well-documented neutral endopeptidase or angiotensin-converting enzyme.
Lecaille
Fabien
F
INSERM U 618, Tours F-37000, France.
Vandier
Christophe
C
Godat
Emmanuel
E
Hervé-Grépinet
Virginie
V
Brömme
Dieter
D
Lalmanach
Gilles
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D001920:Bradykinin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D056657:Cathepsin K; D002403:Cathepsins / Q000008:administration & dosage* / Q000097:blood*; D004338:Drug Combinations; D007022:Hypotension / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D007705:Kinins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D004338:Drug Combinations; D007705:Kinins; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat; D001920:Bradykinin