title: MMP-12 deficiency attenuates angiotensin II-induced vascular injury, M2 macrophage accumulation, and skin and heart fibrosis.
abstract: MMP-12, a macrophage-secreted elastase, is elevated in fibrotic diseases, including systemic sclerosis (SSc) and correlates with vasculopathy and fibrosis. The goal of this study was to investigate the role of MMP-12 in cardiac and cutaneous fibrosis induced by angiotensin II infusion. Ang II-induced heart and skin fibrosis was accompanied by a marked increase of vascular injury markers, including vWF, Thrombospondin-1 (TSP-1) and MMP-12, as well as increased number of PDGFRβ+ cells. Furthermore Ang II infusion led to an accumulation of macrophages (Mac3+) in the skin and in the perivascular and interstitial fibrotic regions of the heart. However, alternatively activated (Arg 1+) macrophages were mainly present in the Ang II infused mice and were localized to the perivascular heart regions and to the skin, but were not detected in the interstitial heart regions. Elevated expression of MMP-12 was primarily found in macrophages and endothelial cells (CD31+) cells, but MMP-12 was not expressed in the collagen producing cells. MMP-12 deficient mice (MMP12KO) showed markedly reduced expression of vWF, TSP1, and PDGFRβ around vessels and attenuation of dermal fibrosis, as well as the perivascular fibrosis in the heart. However, MMP-12 deficiency did not affect interstitial heart fibrosis, suggesting a heterogeneous nature of the fibrotic response in the heart. Furthermore, MMP-12 deficiency almost completely prevented accumulation of Arg 1+ cells, whereas the number of Mac3+ cells was partially reduced. Moreover production of profibrotic mediators such as PDGFBB, TGFβ1 and pSMAD2 in the skin and perivascular regions of the heart was also inhibited. Together, the results of this study show a close correlation between vascular injury markers, Arg 1+ macrophage accumulation and fibrosis and suggest an important role of MMP-12 in regulating these processes.
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stawski
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Haines
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Fine
authors.affiliation: Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland; Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Rudnicka
authors.affiliation: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojanowska
mesh_terms: D000804:Angiotensin II; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D057772:Vascular System Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D017479:Receptors, Platelet-Derived Growth Factor; D053508:Matrix Metalloproteinase 12