title: Whey peptide Isoleucine-Tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta.
abstract: Aortic stiffness is an independent risk factor for development of cardiovascular diseases. Activation of renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) activity leads to overproduction of angiotensin II (ANGII) from its precursor angiotensin I (ANGI). ANGII leads to overexpression and activation of matrix metalloproteinase-2 (MMP2), which is critically associated with pathophysiology of aortic stiffness. We previously reported that the whey peptide Isoleucine-Tryptophan (IW) acts as a potent ACE inhibitor. Herein, we critically elucidate the mechanism of action by which IW causes inhibition of expression and activity of MMP2 in aortic tissue. Effects of IW on expression and activity of MMP2 were assessed on endothelial and smooth muscle cells (ECs and SMCs) in vitro and ex vivo (isolated rat aorta). As controls we used the pharmaceutical ACE inhibitor - captopril and the ANGII type 1 receptor blocker - losartan. In vitro, both ANGII and ANGI stimulation significantly (P<0.01) increased expression of MMP2 assessed with western blot. Similarly, to captopril IW significantly (P<0.05) inhibited ANGI, but not ANGII mediated increase in expression of MMP2, while losartan also blocked effects of ANGII. Signaling pathways regulating MMP2 expression in ECs and SMCs were similarly inhibited after treatment with IW or captopril. In ECs IW significantly (P<0.05) inhibited JNK pathway, whereas in SMCs JAK2/STAT3 pathway, assessed with western blot. In vitro findings were fully consistent with results in isolated rat aorta ex vivo. Moreover, IW not only inhibited the MMP2 expression, but also its activation assessed with gelatin zymography. Our findings demonstrate that IW effectively inhibits expression and activation of MMP2 in rat aorta by decreasing local conversion of ANGI to ANGII. Thus, similar to pharmaceutical ACE inhibitor captopril the dipeptide IW may effectively inhibit ACE activity and prevent the age and hypertension associated rise of aortic stiffness.
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Irakli
authors.initials: I
authors.lastname: Kopaliani
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Zatschler
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Müller
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany. Electronic address: Andreas.Deussen@tu-dresden.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D004151:Dipeptides / Q000008:administration & dosage / Q000737:chemistry* / Q000302:isolation & purification; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D019808:Losartan / Q000008:administration & dosage; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000302:isolation & purification; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D059289:Vascular Stiffness / Q000187:drug effects; D000067816:Whey Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D000067816:Whey Proteins; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2; D019808:Losartan
keywords: Angiotensin II; Angiotensin-converting enzyme; Isoleucine-Tryptophan; Matrix metalloproteinase; Remodeling