Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients.
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ABSTRACT: Background
The mechanisms governing extracellular matrix degradation and smooth muscle cell (SMC) loss in the ascending aorta of bicuspid aortic valve (BAV) patients are unknown. We recently reported that expression and induction of metallothionein, a reactive oxygen species scavenger, is reduced in BAV ascending aortic aneurysms relative to nonaneurysmal patients.Methods
Tissue and primary SMCs from patients with and without thoracic aortic aneurysms and metallothionein-null and wild-type mice were analyzed for cell viability, vascular endothelial growth factor (VEGF), and type I collagen gene expression during exposure to reactive oxygen species.Results
The BAV SMCs and metallothionein -/- mice failed to induce VEGF under conditions of oxidative stress in vitro. Exogenous VEGF restored resistance to oxidative stress in BAV SMCs to normal. Type I collagen gene induction was increased in BAV aorta.Conclusions
Lack of VEGF induction during exposure to reactive oxygen species suggest that the oxidative stress response is faulty upstream of metallothionein and VEGF in BAV SMCs. Improvement of cell viability with VEGF treatment suggests that the deficient pathway can be rescued by VEGF. Increased type I collagen in BAV suggests that lack of metallothionein/VEGF activation in response to reactive oxygen species may play a role in extracellular matrix homeostasis of the ascending aorta. These data continue to support our hypothesis that BAV SMCs lack sufficient resistance to reactive oxygen species to maintain extracellular matrix homeostasis, which imparts a predisposition to thoracic aortic aneurysms.
SUBMITTER: Phillippi JA
PROVIDER: S-EPMC8172083 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundBicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined.MethodsCardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells.ResultsGata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice.ConclusionsThe data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.
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Project description:BackgroundBicuspid aortic valve (BAV) disease leads to deviant helical flow patterns especially in the mid-ascending aorta (AAo), potentially causing wall alterations such as aortic dilation and dissection. Among others, wall shear stress (WSS) could contribute to the prediction of long-term outcome of patients with BAV. 4D flow in cardiovascular magnetic resonance (CMR) has been established as a valid method for flow visualization and WSS estimation. The aim of this study is to reevaluate flow patterns and WSS in patients with BAV 10 years after the initial evaluation.MethodsFifteen patients (median age 34.0 years) with BAV were re-evaluated 10 years after the initial study from 2008/2009 using 4D flow by CMR. Our particular patient cohort met the same inclusion criteria as in 2008/2009, all without enlargement of the aorta or valvular impairment at that time. Flow patterns, aortic diameters, WSS and distensibility were calculated in different aortic regions of interest (ROI) with dedicated software tools.ResultsIndexed aortic diameters in the descending aorta (DAo), but especially in the AAo did not change in the 10-year period. Median difference 0.05 cm/m2 (95% CI: 0.01 to 0.22; P=0.06) for AAo and median difference -0.08 cm/m2 (95% CI: -0.12 to 0.01; P=0.07) for DAo. WSS values were lower in 2018/2019 at all measured levels. Aortic distensibility decreased by median 25.6% in the AAo, while stiffness increased concordantly (median +23.6%).ConclusionsAfter a ten years' follow-up of patients with isolated BAV disease, indexed aortic diameters did not change in this patient cohort. WSS was lower compared to values generated 10 years earlier. Possibly a drop of WSS in BAV could serve as a marker for a benign long-term course and implementation of more conservative treatment strategies.
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