Gene expression differences in cardiovascular disease

The results of three studies about gene expression differences in cardiovascular disease are presented within this thesis. The first topic covers the involvement of the HMGA2 gene in cellular processes found in acute aortic dissection, a disease characterised by the splitting of the aortic layers leading to a high mortality. The results suggest the upregulation of HMGA2 in the endothelium of aortic dissection tissue, accompanied by the transition of these endothelial cells to mesenchymal cells. The second study focuses on differences of the spatial distribution of the eNOS protein within the aorta of patients with bicuspid aortic valve, a common congenital heart defect. The results of this study indicate the spatial dyregulation of the eNOS protein, probably due to an altered hemodynamic, and the associated irregular nitric oxide distribution. The miRNA 208a was quantified in tissue of atrial fibrillation patients in the third study. The miRNA expression was significantly decreased in long-standing persistent atrial fibrillation compared to persistent atrial fibrillation, suggesting a decline over the course of the arrhythmia

Elevation of Matrix Metalloproteinases in Different Areas of Ascending Aortic Aneurysms in Patients with Bicuspid and Tricuspid Aortic Valves

Our aim is to investigate the elevation of matrix proteins in tissues obtained from distal, above the sinotubular junction (proximal), concave, and convex sites of aneurysms in the ascending aorta using a simultaneous multiplex protein detection system. Tissues were collected from 41 patients with ascending aortic aneurysms. A total of 31 patients had a bicuspid aortic valve (BAV), whereas 10 had a tricuspid aortic valve (TAV). Concave and convex aortic site samples were collected from all patients, whereas proximal and distal convexity samples were obtained from 19 patients with BAV and 7 patients with TAV. Simultaneous detection of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was performed at each of the four aortic sites. MMP-2 levels were higher in the concave aortic sites than in the convex aortic sites. In contrast, MMP-8 levels were higher in the convex sites than in the concave sites, as were MMP-9 levels. In both BAV and TAV patients, TIMP-3 levels were higher in the concave sites than in the convex sites. However, TIMP-2 and TIMP-4 levels were significantly elevated in the sinotubular proximal aorta of BAV patients. Simultaneous detection of MMPs and TIMPs revealed different levels at different aortic sites in the same patient

Lung Surfactant Accelerates Skin Wound Healing : A Translational Study with a Randomized Clinical Phase I Study

Lung surfactants are used for reducing alveolar surface tension in preterm infants to ease breathing. Phospholipid films with surfactant proteins regulate the activity of alveolar macrophages and reduce inflammation. Aberrant skin wound healing is characterized by persistent inflammation. The aim of the study was to investigate if lung surfactant can promote wound healing. Preclinical wound models, e.g. cell scratch assays and full-thickness excisional wounds in mice, and a randomized, phase I clinical trial in healthy human volunteers using a suction blister model were used to study the effect of the commercially available bovine lung surfactant on skin wound repair. Lung surfactant increased migration of keratinocytes in a concentration-dependent manner with no effect on fibroblasts. Significantly reduced expression levels were found for pro-inflammatory and pro-fibrotic genes in murine wounds. Because of these beneficial effects in preclinical experiments, a clinical phase I study was initiated to monitor safety and tolerability of surfactant when applied topically onto human wounds and normal skin. No adverse effects were observed. Subepidermal wounds healed significantly faster with surfactant compared to control. Our study provides lung surfactant as a strong candidate for innovative treatment of chronic skin wounds and as additive for treatment of burn wounds to reduce inflammation and prevent excessive scarring. © 2020, The Author(s)

Genexpressionsunterschiede in kardiovaskulären Erkrankungen

The results of three studies about gene expression differences in cardiovascular disease are presented within this thesis. The first topic covers the involvement of the HMGA2 gene in cellular processes found in acute aortic dissection, a disease characterised by the splitting of the aortic layers leading to a high mortality. The results suggest the upregulation of HMGA2 in the endothelium of aortic dissection tissue, accompanied by the transition of these endothelial cells to mesenchymal cells. The second study focuses on differences of the spatial distribution of the eNOS protein within the aorta of patients with bicuspid aortic valve, a common congenital heart defect. The results of this study indicate the spatial dyregulation of the eNOS protein, probably due to an altered hemodynamic, and the associated irregular nitric oxide distribution. The miRNA 208a was quantified in tissue of atrial fibrillation patients in the third study. The miRNA expression was significantly decreased in long-standing persistent atrial fibrillation compared to persistent atrial fibrillation, suggesting a decline over the course of the arrhythmia

Upregulation of the high mobility group AT-hook 2 gene in acute aortic dissection is potentially associated with endothelial-mesenchymal transition

The high mobility group AT-hook 2 (HMGA2) gene is proposed to regulate the genes involved in the epithelial-mesenchymal transition (EMT). One form of EMT is endothelial-mesenchymal transition (EndMT). We analyzed the expression profile of the HMGA2 gene in different human aortic diseases. Aortic specimens were collected from 51 patients, including 19 with acute aortic dissection, 26 with aortic aneurysm, two with Marfan syndrome and four aortic valves. Quantitative real-time polymerase chain reaction was carried out for HMGA2 and immunohistochemical analyses were performed for HMGA2, SNAI1, Vimentin, CD34, MKI-67 and TGFB1. The expression of let-7d microRNA, which is assumed to play a role in the regulation of HMGA2, was also quantified. The level of HMGA2 gene expression was significantly higher in acute aortic dissection compared with all the other samples (193.1 vs. 8.1 fold normalized to calibrator, P<0.001). The immunohistochemical investigation showed that HMGA2, SNAI1, and Vimentin proteins were mainly detected in the endothelial cells of the vasa vasorum. The HMGA2 gene is upregulated in acute aortic dissection. This is the first report describing a link between HMGA2 and acute aortic dissection. The HMGA2, SNAI1 and Vimentin proteins were mainly detected in the endothelium of the vasa vasorum. It seems that HMGA2 overexpression in acute aortic dissection occurs in a let-7d-independent manner and is associated with EndMT of the vasa vasorum