Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-β activation.
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.


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.
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.
Valentina
V
Paloschi
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.).
Jesper R
JR
Gådin
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.).
Shaukat
S
Khan
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.).
Hanna M
HM
Björck
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.).
Lei
L
Du
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.).
Shohreh
S
Maleki
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.).
Joy
J
Roy
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.).
Jan H M
JH
Lindeman
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.).
Salah A
SA
Mohamed
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.).
Takeshi
T
Tsuda
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.).
Anders
A
Franco-Cereceda
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.).
Per
P
Eriksson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001014:Aortic Aneurysm / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006349:Heart Valve Diseases / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D025341:Principal Component Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
aneurysm; bicuspid aortic valve