Open AccessAnatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation
Author(s) -
Emrich Fabian,
Penov Kiril,
Arakawa Mamoru,
Dhablania Nathan,
Burdon Grayson,
Pedroza Albert J.,
Koyano Tiffany K.,
Kim Young M.,
Raaz Uwe,
Connolly Andrew J.,
Iosef Cristiana,
Fischbein Michael P.
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14587
Subject(s) - apocynin , elastin , angiotensin ii , nadph oxidase , chemistry , reactive oxygen species , zymography , marfan syndrome , aneurysm , adventitia , aorta , pathology , matrix metalloproteinase , biochemistry , medicine , receptor , surgery
Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1 C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin‐enhanced chemiluminescence (LGCL), Verhoeff's elastin‐Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1 C1039G/+ AS‐ or DES‐derived smooth muscle cells (SMC) were treated with anti‐TGF‐β antibody, angiotensin II (AngII), anti‐TGF‐β antibody + AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1 C1039G/+ AS aorta, but absent in normal‐sized DES aorta. Fbn1 C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1 C1039G/+ ‐derived AS SMC had increased NADPH activity compared to DES‐derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF‐β dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF‐β dependent.