Project description:Aneurysmatic and dissection cells show a specific alteration of gene expression, which allow a disease specific distinction. We used microarrays to analyse the cellular gene expression of controls, thoracic aortic aneurysm, and aortic dissection.
Project description:Conducted proteomics on samples from patients with aortic aneurysm and from non-dilated controls. Furthermore, we investigated both patients with bicuspid aortic valves (BAV) and also the more normal tricuspid aortic valves (TAV). The aim was to elucidate the molecular mechanisms behind the higher propensity of BAV patients to develop aorta dilation and consequent aortic aneurysm.
Project description:The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. We found that miR-1204 was significantly increased in both plasma and aorta of elder patients with AAD, and was positively correlated with age. Cell senescence induced the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induced vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop.
Project description:Although abnormal TGFbeta signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, the precise role of TGFbeta signaling in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to investigate the role of TGFbeta signaling in molecular pathways of pathogenesis associated with development of aortic aneurysm and aortic rupture. This study reports an isoform-specific effect of TGFbeta in MFS aortic disease and the effects of deleting the first hybrid domain of fibrillin-1 on TGFbeta signaling. Distinct molecular differences in mouse models of aneurysm (Fbn_GT-8_plus), of aneurysm and rupture (Fbn1_GT-8_H1delta), and of microdissection (Fbn1_H1delta_plus) were identified, which associated with TGFbeta signaling and extracellular matrix composition, possibly contributing to the development of dissection and rupture. These findings offer new insights into the pathophysiological mechanisms that potentially drive initiation of aortic dissection and could pave the way for development of new treatment targets of aortic disease.
Project description:Genetic risk factors play a fundamental role in the etiology of thoracic aortic aneurysm and dissection (TAAD). More than 40 disease or risk genes for connective tissue disorders (CTD) characterized by TAAD have been described, however, about 70% of patients genetically remain undiagnosed. We aimed to identify novel sequence variants involved in the etiology of TAAD. Exome sequencing in three affected members of a family with TAAD identified the missense variant CDKL1 c.430T>C p.(Cys144Arg). Gene panel sequencing of 420 individuals with TAAD spectrum disorders revealed three CDKL1 missense variants, c.407C>T p.(Thr136Met) in an individual with aortic dissection, c.423T>G p.(Ile141Met) in a patient with aortic aneurysm and skeletal anomalies, as well as c.620C>T p.(Ser207Leu) in two siblings with ectasia of the aortic bulb, Marfan syndrome-like features and a family history of TAAD. Furthermore, exome sequencing identified the c.335T>C p.(Leu112Pro) missense variant in a female with bilateral vertebral artery dissection. CDKL1 encodes a barely investigated serine/threonine protein kinase involved in ciliary biology and cyclic guanosine monophosphate (cGMP) signaling. The predicted amino acid substitutions localize adjacent to/in the ATP binding domain [p.(Thr136Met), p.(Ile141Met) and p.(Cys144Arg)] or substrate-binding motifs [p.(Leu112Pro), p.(Ser207Leu)] of CDKL1. Knockdown of zcdkl1 in zebrafish lead to malformations of inter somatic vessels (ISV). Co-injection of human CDKL1WT RNA, but not of CDKL1C144R and CDKL1S207L RNA rescued ISV malformations. CDKL1 p.Cys144Arg-, p.Ser207Leu-, and p.Thr136Met expressed in heterologous cells interfered with CDKL1 kinase function and resulted in significantly altered kinase profiles compared to CDKL1WT protein. Kinase upstream analysis suggested a hyper-activation of nitric oxide (NO)-cGMP-protein kinase G (PRKG)-mediated and calcium (Ca2+)/calmodulin (CaM)-depending cellular signaling routes. Furthermore, disease-associated variants interfered with the length of primary cilia and the localization of CDKL1 at primary cilia, and it affected overall protein-complexing/protein-protein binding properties of CDKL1, especially with proteins involved in intraflagellar transport to cilia. Finally, expression of endogenous CDKL1 was demonstrated in cells positive for the multipotential mesenchymal stromal cell/multipotential precurser cell marker STRO-1 around Vasa vasorum in human aortic tissue. Taken together, genetic, clinical and functional data strongly suggest a role of CDKL1 variants in the pathogenesis of CTD with pronounced vascular involvement. Our data highlight that dysregulated signaling through NO, cGMP, and PRKG is critical to the etiology of TAAD/arterial dissection.
Project description:To determine how gene expression is altered in aorta tissue in response to aortic aneurysm disease. Thoracic or abdominal aorta tissue was isolated from patients requiring surgery due to aortic aneurysm or other (control) reason.
Project description:Conducted proteomics on samples from patients with aortic aneurysm and from non-dilated controls. Furthermore, we investigated both patients with bicuspid aortic valves (BAV) and also the more normal tricuspid aortic valves (TAV). The aim was to elucidate the molecular mechanisms behind the higher propensity of BAV patients to develop aorta dilation and consequent aortic aneurysm.
Project description:The aim of this study was to assess the relative gene expression in human AAA and AOD. Genome-wide expression analysis of abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) specimens obtained from 20 patients with small AAA (mean maximum aortic diameter=54.3±2.3 mm), 29 patients with large AAA (mean maximum aortic diameter=68.4±14.3 mm), and 9 AOD patients (mean maximum aortic diameter=19.6±2.6 mm). Relative aortic gene expression was compared with that of 10 control aortic specimen of organ donors.
Project description:To discover novel biomarkers for aortic aneurysm, serum samples of patients with thoracic aortic aneurysm were fractionated, tryptic digested, and subjected to proteome analysis.
Project description:Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.