PubMed · 14095666
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H MOERL. 1963. [AORTIC SEPTAL DEFECT].. https://pubmed.ncbi.nlm.nih.gov/14095666/
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Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-gamma-induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-gamma dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma. Moreover, simvastatin lowers the IFN-gamma-induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-gamma-induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-gamma stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis.
C-reactive protein (CRP) contributes to the process of atherosclerosis by inducing pro-inflammatory changes in endothelial cells. However, the exact receptor involved in CRP-induced endothelial changes remains unclear. Human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were used for the experiments. After incubation with CRP, immunoblotting showed a significant decrease of IkappaB protein and electrophoretic mobility shift assay showed a significant increase of nuclear NF-kappaB binding capacity. These changes were associated with a significant increase of vascular cell adhesion molecule-1 (VCAM-1) expression. The mRNA level of CD32, the major binding protein for CRP in endothelial cells, increased significantly as measured by Northern blot and Western blot. When these cells were transfected with siRNA directed against CD32, the mRNA of CD32 decreased significantly. The IkappaB degradation, NF-kappaB nuclear translocation and VCAM-1 up-regulation induced by CRP were all inhibited by treatment with siRNA against CD32. SB203580, a P38 inhibitor, significantly attenuated the CRP-induced responses while SP600125 (c-jun kinase inhibitor) did not. In conclusion, CRP-induced IkappaB degradation, NF-kappaB nuclear translocation and VCAM-1 protein expression in HUVECs and HAECs. CRP also increased the expression of CD32, which might serve as the receptor for CRP in endothelial cells and mediated the effects of CRP.
BACKGROUND: Different anatomical forms of proximal aortic dilations associated with aortic valve disease can be distinguished by echocardiography. Differences in the anatomy could reflect different pathogeneses and need for different therapeutic approaches. The present study assessed the clinical features associated to each anatomical form, particularly focusing on the relations with valve morphology and function. METHODS: Trans-thoracic and trans-esophageal echocardiography reports of 552 adult patients (mean age 60.4+/-12.8 years; 379 male) with mild to severe proximal aorta dilation were reviewed. The relationships between the anatomy of aorta dilatation (distinguished into "root type" dilatation, with maximal enlargement at the sinuses, and "mid-ascending type", with maximal diameter at the mid-ascending tract) and aortic valve morphology (tricuspid/bicuspid) and function (normal/stenosis/regurgitation) were assessed. The relations with other clinico-echocardiographic variables were also tested in univariate and multivariate analysis. RESULTS: A "root type" dilatation was found in 4.9% tricuspid patients with stenosis, 32.3% with regurgitation, 22.5% with normal valve function (p=0.018). Dilatation prevailed at the mid-ascending tract in patients with bicuspid aortic valve, irrespective of valve function (stenotic: 92.9%, regurgitant: 87.9%, normal: 94.3%; p=0.23). Predominant root involvement was significantly more prevalent in male patients (24.8% versus 5.2% in females; p<0.001). In multivariate analysis, predominant aortic valve regurgitation (OR=1.83; p=0.028) independently predicted root site, while predominant aortic valve stenosis (OR=3.70; p=0.001), bicuspidity (OR=2.90; p=0.005) and female sex (OR=6.10; p<0.001) predicted mid-ascending site. CONCLUSIONS: Pathogenetical considerations arise from the evidence of preferential mid-ascending localization of bicuspid-associated aortic dilatations. This finding is consistent with previous studies on bicuspid valve models revealing a wall stress overload beyond the sino-tubular ridge.