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New insights into the role of inducible nitric oxide synthase in Marfan syndrome associated aortic aneurysm
Author(s) -
Talley Nicholas,
Hoxha Brikena,
Alexander Tia,
Cameron Eryn L.,
VallejoElias Johana,
Esfandiarei Mitra
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.843.26
Subject(s) - marfan syndrome , fibrillin , bicuspid aortic valve , medicine , enos , cardiology , nitric oxide synthase , aorta , elastin , endothelial dysfunction , aortic dissection , aneurysm , extracellular matrix , nitric oxide , chemistry , pathology , surgery , biochemistry
Marfan syndrome (MFS) is an autosomal dominant inherited disease that affects the connective tissue of large vessels throughout the human body. MFS is caused by mutations in the FBN1 gene which encodes for fibrillin‐1, a major component of extracellular microfibrils and acts as a scaffolding protein for elastin deposition, and allows for the formation of elastic fibers in the extracellular matrix of large arteries. The loss of aortic wall structural integrity leads to cardiovascular manifestations of MFS, which include the dilation of the aortic root that can lead to dissection and rupture. Previous studies have shown that the activity of endothelial nitric oxide (eNOS) has decreased in the aortic wall leading to endothelial dysfunction in MFS mice. However, we have been able to show that despite an obvious decrease in eNOS activity, the basal NO level in the aortic tissue is significantly higher in MFS mice aorta. Therefore, we aim to further determine the role that inducible nitric oxide synthase (iNOS) may play in MFS aneurysm pathogenesis by creating a MFS mouse lacking iNOS expression. In this study, wild type C75BL/6, MFS ( FBN +/− ) and MFS mice lacking iNOS expression ( FBN+/−, iNOS−/− ) were subjected to high resolution, high frequency ultrasound imaging at the age of 3 and 6 months to evaluate various cardiac and aortic parameters including aortic diameter, pulse wave velocity, cardiac ejection fraction & stroke volume, left ventricular wall thickness and mass and mitral valve early and atrial velocities (E/A) ratio. Our data shows that aortic root diameters at the aortic annulus and sinus of Valsalva, aortic pulse wave velocity, and mitral valve early velocity were greater in 3‐month old MFS mice when compared to control and MFS mice lacking iNOS expression, indicating a significant increase in aortic wall stiffness in MFS mice aorta. At 6 months of age, mitral valve early and atrial velocities and E/A ration were significantly decreased in MFS mice compared to controls and MFS mice lacking iNOS expression. In addition, measurements for aortic annulus diameter, ejection fraction, fractional shortening were markedly increased in 6‐month old MFS mice as compared to control and MFS mice lacking iNOS expression. These findings indicate that inhibition of iNOS may have some protective effects in the cardiovascular system in MFS mice, and therefore, providing valuable information about the potential therapeutic value of iNOS inhibition on cardiac and aortic function and structure in the mouse model of MFS associated aortic aneurysm. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .