Valentina Paloschi1, Jesper R Gådin2, Shaukat Khan2, Hanna M Björck2, Lei Du2, Shohreh Maleki2, Joy Roy2, Jan H M Lindeman2, Salah A Mohamed2, Takeshi Tsuda2, Anders Franco-Cereceda2, Per Eriksson2. 1. From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine (V.P., J.R.G., H.M.B., L.D., S.M., P.E.), Vascular Surgery Section, Department of Molecular Medicine and Surgery (J.R.), and Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Center for Cardiac Research, Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE (S.K., T.T.); Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (J.H.M.L.); and Department of Cardiac Surgery, University Clinic of Schleswig-Holstein Campus Luebeck, Luebeck, Germany (S.A.M.). Valentina.Paloschi@ki.se. 2. From the Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine (V.P., J.R.G., H.M.B., L.D., S.M., P.E.), Vascular Surgery Section, Department of Molecular Medicine and Surgery (J.R.), and Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery (A.F.-C.), Karolinska Institutet, Stockholm, Sweden; Center for Cardiac Research, Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE (S.K., T.T.); Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands (J.H.M.L.); and Department of Cardiac Surgery, University Clinic of Schleswig-Holstein Campus Luebeck, Luebeck, Germany (S.A.M.).
Abstract
OBJECTIVE: Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysms. Transforming growth factor-β (TGFβ) is a crucial factor of vascular remodeling, the impaired signaling of which can alter the structure and composition of the extracellular matrix. In this study, we analyzed the activity of TGFβ in aneurysmal and nonaneurysmal ascending aorta from BAV patients, using tricuspid aortic valve (TAV) patients as a reference group. APPROACH AND RESULTS: The response to exogenous TGFβ was analyzed with regard to gene expression in primary aortic smooth muscle cells that were isolated from 7 BAV and 5 TAV patients and in valve fibroblasts from 7 BAV and 8 TAV patients. The set of genes that were significantly changed by TGFβ (217 genes) was compared with gene expression profiles of the ascending aorta from BAV and TAV patients (139 arrays). By principle component analysis, based on the 217 genes, gene expression differed significantly in the intima/media region between aneurysmal BAV and TAV aortas, driven by the response in TAV patients. During aneurysm development the levels of phosphorylated SMADs and the availability of free TGFβ were lower in BAV patients compared with TAV. Confocal microscopy analysis showed a higher colocalization of latency associated peptide and latent TGFβ binding protein 3 in BAV aortas. CONCLUSIONS: Our findings suggest that TGFβ activation during aneurysm formation is muted in patients with BAV, possibly as a result of an increased TGFβ sequestration in the extracellular space.
OBJECTIVE:Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysms. Transforming growth factor-β (TGFβ) is a crucial factor of vascular remodeling, the impaired signaling of which can alter the structure and composition of the extracellular matrix. In this study, we analyzed the activity of TGFβ in aneurysmal and nonaneurysmal ascending aorta from BAV patients, using tricuspid aortic valve (TAV) patients as a reference group. APPROACH AND RESULTS: The response to exogenous TGFβ was analyzed with regard to gene expression in primary aortic smooth muscle cells that were isolated from 7 BAV and 5 TAV patients and in valve fibroblasts from 7 BAV and 8 TAV patients. The set of genes that were significantly changed by TGFβ (217 genes) was compared with gene expression profiles of the ascending aorta from BAV and TAV patients (139 arrays). By principle component analysis, based on the 217 genes, gene expression differed significantly in the intima/media region between aneurysmal BAV and TAV aortas, driven by the response in TAV patients. During aneurysm development the levels of phosphorylated SMADs and the availability of free TGFβ were lower in BAV patients compared with TAV. Confocal microscopy analysis showed a higher colocalization of latency associated peptide and latent TGFβ binding protein 3 in BAV aortas. CONCLUSIONS: Our findings suggest that TGFβ activation during aneurysm formation is muted in patients with BAV, possibly as a result of an increased TGFβ sequestration in the extracellular space.
Authors: Sebastian Albinsson; Alessandro Della Corte; Azra Alajbegovic; Katarzyna K Krawczyk; Ciro Bancone; Umberto Galderisi; Marilena Cipollaro; Marisa De Feo; Amalia Forte Journal: Heart Vessels Date: 2017-01-19 Impact factor: 2.037
Authors: Michael A Borger; Paul W M Fedak; Elizabeth H Stephens; Thomas G Gleason; Evaldas Girdauskas; John S Ikonomidis; Ali Khoynezhad; Samuel C Siu; Subodh Verma; Michael D Hope; Duke E Cameron; Donald F Hammer; Joseph S Coselli; Marc R Moon; Thoralf M Sundt; Alex J Barker; Michael Markl; Alessandro Della Corte; Hector I Michelena; John A Elefteriades Journal: J Thorac Cardiovasc Surg Date: 2018-08 Impact factor: 5.209
Authors: Shohreh Maleki; Sanela Kjellqvist; Valentina Paloschi; Joelle Magné; Rui Miguel Mamede Branca; Lei Du; Kjell Hultenby; Johan Petrini; Jonas Fuxe; Janne Lehtiö; Anders Franco-Cereceda; Per Eriksson; Hanna M Björck Journal: Sci Rep Date: 2016-10-25 Impact factor: 4.379
Authors: Elena Ignatieva; Daria Kostina; Olga Irtyuga; Vladimir Uspensky; Alexey Golovkin; Natalia Gavriliuk; Olga Moiseeva; Anna Kostareva; Anna Malashicheva Journal: Front Physiol Date: 2017-07-25 Impact factor: 4.566