Further, qRT-PCR and ChIP analyses showed lower expression of miR-200c, higher expression of miR-200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR-200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR-200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT).
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.
BAV TAA samples showed an increased concentration of putrescine and spermidine vs. TAV and donor samples, together with a decreased mRNA level of polyamine anabolic enzymes and of the putative polyamine transporter SLC7A1/CAT-1.
Two overexpressed genes in the TAV group, osteopontin (OPN) and tenascin C (TNC), were consistently more highly expressed in TAV aneurysms than in BAV aneurysms and normal aortas as determined by real-time reverse transcriptase quantitative polymerase chain reaction and immunohistochemistry.
Among these factors, dyslipidemia (i.e., high LDL cholesterol, high lipoprotein (a)) and the activation of specific pro-inflammatory pathways (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 inflammasome and Toll-like receptor 4) appear to play a pivotal role in the progression of BAV-associated diseases.
Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p < 0.0001 by ANOVA test).
We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.
The purpose of our study was to investigate the potential contribution of germline mutations in NOTCH1, GATA5 and TGFBR1 and TGFBR2 genes in a cohort of Italian patients with familial Bicuspid Aortic Valve (BAV).
Nine genes previously associated with BAV (NOTCH1, AXIN1, EGFR, ENG, GATA5, NKX2-5, NOS3, PDIA2, and TGFBR2) were sequenced in 48 patients with BAV using the Ion Torrent Personal Genome Machine.
Because bicuspid aortic valve (BAV) is a congenital heart defect in patients with Loeys-Dietz syndrome, this study was conducted to investigate whether variants in TGFBR1 or TGFBR2 are responsible for sporadic BAV.
Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., <i>GATA5, NOS3</i>) or in syndromic (e.g., <i>TGFBR1/2, TGFB2/3</i>) or non-syndromic (e.g., <i>ACTA2</i>) TAA forms.