Angiotensin I-converting enzyme inhibitor peptides derived from the endostatin-containing NC1 fragment of human collagen XVIII

Abstract

Extracellular matrix and soluble plasma proteins generate peptides that regulate biological activities such as cell growth, differentiation and migration. Bradykinin, a peptide released from kininogen by kallikreins, stimulates vasodilatation and endothelial cell proliferation. Various classes of substances can potentiate these biological actions of bradykinin. Among them, the best studied are bradykinin potentiating peptides (BPPs) derived from snake venom, which can also strongly inhibit angiotensin I-converting enzyme (ACE) activity. We identified and synthesized sequences resembling BPPs in the vicinity of potential proteolytic cleavage sites in the collagen XVIII molecule, close to endostatin. These peptides were screened as inhibitors of human recombinant wild-type ACE containing two intact functional domains; two full-length ACE mutants containing only a functional C- or N-domain catalytic site; and human testicular ACE, a natural form of the enzyme that only contains the C-domain. The BPP-like peptides inhibited ACE in the micromolar range and interacted preferentially with the C-domain. The proteolytic activity involved in the release of BPP-like peptides was studied in human serum and human umbilical-vein endothelial cells. The presence of enzymes able to release these peptides in blood led us to speculate on a physiological mechanism for the control of ACE activities.

Cysteine Cathepsins S and L Modulate Anti-angiogenic Activities of Human Endostatin

“…Cathepsins L and S cleaved Endo-08 and Endo-09 between residues His-1344 and Leu-1345, and Endo-10 between Ala-1347 and Leu-1348 (human collagen XVIII numbering). These findings are in agreement with the previously proposed cleavage sites of the NC-1 domain, but they do not match any of N-terminal forms of circulating endostatin that have been characterized (9,19,20). However, cathepsin B cleaved Endo-09 between Leu-1345 and Val-1346, which does correspond to the N terminus of the shorter molecular variety of endostatin (ϳ20 kDa) found in human plasma for which no other candidate protease has been identified to date (9).…”

Inhibition of Endostatin/Collagen XVIII Deteriorates Left Ventricular Remodeling and Heart Failure in Rat Myocardial Infarction Model

“…34 Interestingly, a recent study showed that the internal peptide sequence of endostatin resembles an ACE-inhibitory peptide, called bradykininpotentiating peptide, and that the synthetic peptide of the sequence indeed inhibited ACE catalytic activity. 23,24,35 Thus, endostatin or its degraded peptide fragments are implicated as a putative ACEI. Taking all the evidence together, endostatin is a negative regulator of protease-mediated adverse tissue remodeling in the infarcted heart.…”

New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart

“…158) Various ACE inhibitory peptides derived from animals and plants have been found. 159) An amino acid sequence of the NC1 domain of type XVIII collagen in the vicinity of endostatin resembles the snake venom-derived bradykinin-potentiating peptides, which strongly inhibit ACE activity. 160) Isobe et al reported that an anti-endostatin antibody increased ACE activity in the infarcted myocardium.…”