Importance of the N‐terminal site of angiotensin converting enzyme and AcSDKP in the control of fibrosis

Abstract

Bleomycin is a potent anticancer agent, but its administration is limited by bleomycin-induced lung fibrosis. Inhibition of the renin-angiotensin system has been suggested to decrease bleomycin toxicity, but the efficacy of such strategies remains uncertain and somewhat contradictory. Our hypothesis is that, besides angiotensin II, other substrates of angiotensin-converting enzyme (ACE), such as AcSDKP, play a significant role in controlling fibrosis. We studied bleomycin-induced lung injury in normotensive mice, termed N-KO and C-KO, which have point mutations inactivating either the N- or C-terminal catalytic sites of ACE. N-KO, but not C-KO mice, have a marked resistance to bleomycin lung injury. To determine the importance of the ACE N-terminal peptide substrate AcSDKP in the resistance to bleomycin injury, N-KO mice were treated with S-17092, an inhibitor of the release of AcSDKP. In response to bleomycin injection, S-17092-treated N-KO mice developed lung fibrosis similar to WT mice. In contrast, the administration of AcSDKP to WT mice reduced bleomycin-induced lung fibrosis. We show that the inactivation of the N-terminal catalytic site of ACE significantly reduced bleomycin-induced lung fibrosis and implicates AcSDKP in the mechanism of protection. These data suggest a possible means to increase tolerance to bleomycin and to treat fibrosing lung diseases.