title: Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome.
abstract: OBJECTIVE
  Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome.
  
  
  RESULTS
  Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs.
  
  
  CONCLUSIONS
  Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Fabian C
authors.initials: FC
authors.lastname: Emrich
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Homare
authors.initials: H
authors.lastname: Okamura
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Alex R
authors.initials: AR
authors.lastname: Dalal
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Kiril
authors.initials: K
authors.lastname: Penov
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Denis R
authors.initials: DR
authors.lastname: Merk
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Uwe
authors.initials: U
authors.lastname: Raaz
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hennigs
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Jocelyn T
authors.initials: JT
authors.lastname: Chin
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Miquell O
authors.initials: MO
authors.lastname: Miller
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Pedroza
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Juliana K
authors.initials: JK
authors.lastname: Craig
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Tiffany K
authors.initials: TK
authors.lastname: Koyano
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Francis G
authors.initials: FG
authors.lastname: Blankenberg
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Mohr
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alvira
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.).
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.affiliation: From the Department of Cardiothoracic Surgery (F.C.E., H.O., A.R.D., K.P., D.R.M., J.T.C., M.O.M., A.J.P., J.K.C., T.K.K, M.P.F.), Department of Cardiovascular Medicine (U.R.), Department of Pediatrics (J.K.H., C.M.A, M.R.), Department of Radiology (F.G.B.), and Department of Pathology (A.J.C.), Stanford University, CA; Department of Cardiothoracic Surgery, Heart Center, Leipzig University, Leipzig, Germany (F.C.E., K.P., D.R.M., F.W.M.); and Department of Cardiovascular Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan (H.O.). mfischbe@stanford.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fischbein
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D001014:Aortic Aneurysm / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005455:Fluorescent Antibody Technique; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000235:genetics; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D066253:Vascular Remodeling / Q000187:drug effects; D054392:Adipokines
chemical_list: D061945:Caspase Inhibitors; D020169:Caspases; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Marfan syndrome; aneurysm; apoptosis; caspases; extracellular matrix