Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation

Abstract

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 Fbn1C1039G/+ 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. Fbn1C1039G/+ 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 Fbn1C1039G/+ AS aorta, but absent in normal‐sized DES aorta. Fbn1C1039G/+ 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 Fbn1C1039G/+‐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.

Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome

“…Elastica van Gieson staining was used to visualize the aortic elastic fiber structure. Elastic fiber breaks were defined as the presence of discernable breaks of continuous elastin fiber and counted circumferentially in all laminae [ 16 , 17 ]. Rat anti-mouse monoclonal F4/80 antibody (MCA497; Bio-Rad) was used for immunohistochemical staining to recognize macrophages at the dilution of 1:200.…”

Oxidative stress in genetically triggered thoracic aortic aneurysm: role in pathogenesis and therapeutic opportunities

“…Studies using MFS mice have demonstrated impaired aortic contraction and relaxation of the aorta in vivo, with increased lipid peroxidation, increased pro-oxidant enzyme expression and decreased expression of the major ROS-clearing antioxidant, superoxide dismutase (SOD), within the aortic wall [ 16 ]. Furthermore, increased ROS production has shown to be limited only to the aneurysmal site and not extending to normal aortic tissue distally [ 35 ]. Importantly, restoration of normal redox homeostasis with respective treatments (ROS inhibition or antioxidant supplementation) improved vasomotor function and attenuated aneurysmal dilatation, providing scope for ROS as a future therapeutic target.…”

Aortic Dilatation in Patients With Bicuspid Aortic Valve

“…Therapies that inhibit or attenuate TGF-β signaling pathway expression are recognized in patients with MFS. Beta-blockers, as well as ARBs, have been shown to be effective in preventing and slowing the progression of aortic dilation in patients with MFS ( Baumgartner et al, 2010 ; Lindsay and Dietz, 2011 ; Emrich et al, 2019 ). ARBs have been shown to neutralize or attenuate TGF-β signaling pathway expression, such as irbesartan and losartan, and are as important as beta-blockers in slowing aortic dilatation and reducing aortic dilatation rates ( Cohn et al, 2007 ; Lindsay and Dietz, 2011 ; Emrich et al, 2019 ).…”