title: Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment.
abstract: Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages. Mstn co-localized with α-smooth muscle actin (α-SMA) staining and with some CD45+ cells, indicating Mstn expression in VSMCs and bloodstream-derived leukocytes. In vitro, Mstn was tested in VSMCs and monocytes. In A7r5 VSMCs, Mstn downregulated proliferation and Smoothelin mRNA, induced cytoskeletal rearrangement, increased migratory rate and MCP-1/CCR2 expression. In monocytes (THP-1 cells and human monocytes), Mstn acted as a chemoattractant and increased the MCP-1-dependent chemotaxis, F-actin, α-SMA, MCP-1 and CCR2 expression; in turn, MCP-1 increased Mstn mRNA. Mstn induced JNK phosphorylation both in VSMCs and monocytes. Our results indicate that Mstn is overexpressed in abdominal aortic wall deterioration, affects VSMCs and monocyte biology and sustains a chronic inflammatory milieu. These findings propose to consider Mstn as a new playmaker in atherosclerosis progression.
authors.affiliation: Nephrology Division, Department of Internal Medicine, IRCCS University Hospital San Martino, University of Genova, Genova, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Verzola
authors.affiliation: Nephrology Division, Department of Internal Medicine, IRCCS University Hospital San Martino, University of Genova, Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Milanesi
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genova, viale Benedetto XV, 6, 16132 Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bertolotto
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Garibaldi
authors.affiliation: Nephrology Division, Department of Internal Medicine, IRCCS University Hospital San Martino, University of Genova, Genova, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Villaggio
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Brunelli
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Balbi
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ameri
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genova, viale Benedetto XV, 6, 16132 Genova, Italy.|IRCCS AOU San Martino-IST, Genova, largo Benzi 10 16143 Genova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Unit of Vascular and Endovascular Surgery, University of Genova, Genova, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Palombo
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ghigliotti
authors.affiliation: Nephrology Division, Department of Internal Medicine, IRCCS University Hospital San Martino, University of Genova, Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Garibotto
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: Division of Cardiology, IRCCS University Hospital San Martino, Research Centre of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Barisione
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D055435:Myostatin / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D000074084:THP-1 Cells
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D003598:Cytoskeletal Proteins; C525911:MSTN protein, human; D009124:Muscle Proteins; D055435:Myostatin; C100762:SMTN protein, human