Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm

Nataatmadja, M., West, M., West, J., Summers, K., Walker, P., Nagata, M. and Watanabe, T. (2003) Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation, 108 10: 329-334.

Document type:	Journal Article
Collections:	Excellence in Research Australia (ERA) - Collection School of Medicine Publications

Author(s)	Nataatmadja, M. West, M. West, J. Summers, K. Walker, P. Nagata, M. Watanabe, T.
Title	Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm
Journal name	Circulation
Publication date	2003
Sub-type	Article
Volume number	108
Issue number	10
ISSN	0009-7322
Start page	329
End page	334
Total pages	6
Editor(s)	J. T. Willerson
Place of publication	Philadelphia
Publisher	Lippincott Williams & Wilkins
Collection year	2003
Language	eng
Subject	C1 321003 Cardiology (incl. Cardiovascular Diseases) 730106 Cardiovascular system and diseases
Abstract	Background - Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)- 2 in VSMC apoptosis was studied in MS aneurysm. Methods and Results - Aneurysm tissue was obtained from patients undergoing surgery ( MS: 4 M, 1 F, age 27 - 45 years; BAV: 3 M, 2 F, age 28 - 65 years). Normal aorta from subjects with nonaneurysm disease was also collected ( 4 M, 1 F, age 23 - 93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs. There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS ( 27 +/- 8%) and BAV ( 32 +/- 14%) compared with control ( 7 +/- 5%). Conclusions - In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.
Keyword(s)	Cardiac & Cardiovascular Systems Hematology Peripheral Vascular Disease Aneurysm Apoptosis Congenital Heart Disease Tenascin-c Fibrillin Fibroblasts Dissections Mechanisms
Additional Notes	The paper contains immunohistochemical studies of the pathology of aortic aneurysm and challenges the accepted role of inflammation in aortic aneurysm resulting from genetic factors. Nagata and Watanabe are Japanese collaborators.