A possible alternative mechanism of kinin generation in vivo by cathepsin L.
We investigated the ability of cathepsin L to induce a hypotensive effect after intravenous injection in rats and correlated this decrease in blood pressure with kinin generation. Simultaneously with blood pressure decrease, we detected plasma kininogen depletion in the treated rats. The effect observed in vivo was abolished by pre-incubation of cathepsin L with the cysteine peptidase-specific inhibitor E-64 (1 microM) or by previous administration of the bradykinin B2 receptor antagonist JE049 (4 mg/kg). A potentiation of the hypotensive effect caused by cathepsin L was observed by previous administration of the angiotensin I-converting enzyme inhibitor captopril (5 mg/kg). In vitro studies indicated that cathepsin L excised bradykinin from the synthetic fluorogenic peptide Abz-MTSVIRRPPGFSPFRAPRV-NH2, based on the Met375-Val393 sequence of rat kininogen (Abz = o-aminobenzoic acid). In conclusion, our data indicate that in vivo cathepsin L releases a kinin-related peptide, and in vitro experiments suggest that the kinin generated is bradykinin. Although it is well known that cysteine proteases are strongly inhibited by kininogen, cathepsin L could represent an alternative pathway for kinin production in pathological processes.
Puzer
Luciano
L
Department of Biophysics, Escola Paulista de Medicina, UNIFESP, Rua 3 de Maio 100, 04044-020, São Paulo, Brazil.
Vercesi
Juliana
J
Alves
Marcio F M
MF
Barros
Nilana M T
NM
Araujo
Mariana S
MS
Aparecida Juliano
Maria
M
Reis
Marina L
ML
Juliano
Luiz
L
Carmona
Adriana K
AK
D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D007705:Kinins / Q000378:metabolism*; D008969:Molecular Sequence Data; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000959:Antihypertensive Agents; D007705:Kinins; C065679:icatibant; D002216:Captopril; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534280:Ctsl protein, rat; D001920:Bradykinin