Fibrinogen and factor VII promoter polymorphisms in women with preeclampsia

OBJECTIVE: To determine whether genetic variability in the promoter regions of the genes encoding fibrinogen and factor VII contribute to individual differences in susceptibility to the development of preeclampsia. METHODS: The study involved 133 preeclamptic and 115 healthy control pregnant women who were genotyped for the G-455A polymorphism in the beta-fibrinogen gene promoter and for a decamer insertion or deletion polymorphism at position -323 in the factor VII gene promoter. We used chi(2) analysis to assess genotype frequency differences between preeclamptic women and controls. RESULTS: The allelic distribution of the fibrinogen A-455G polymorphism was similar in the two groups, with the frequency of the variant A allele being 18.8% in the preeclampsia group and 20.9% in the control group. We did not find any association between the presence of the factor VII insertion allele and preeclampsia (5.6% versus 6.1%). Accordingly, the genotype distribution of the fibrinogen G-455A and factor VII polymorphisms in the preeclamptic and control groups was similar (P =.852 and P =.308). CONCLUSION: The G-455A polymorphism of the fibrinogen gene promoter and the decamer insertion or deletion polymorphism of the factor VII gene promoter are unlikely to be major genetic predisposing factors for preeclampsia in subjects from eastern Finland.     

MMP-1 (collagenase-1) expression in primary colorectal cancer and its metastases

OBJECTIVE: The role of MMP-1 (collagenase-1) in the development of a metastatic phenotype in colorectal cancer (CRC) has not been fully studied. The aim of this study was to investigate the mechanisms involved in the dissemination of CRC by examining the expression of MMP-1 in the primary tumours and their metastases, with special reference to standard clinicopathological features and disease outcome. MATERIAL AND METHODS: Surgical specimens from the primary tumours (P) and their metastatic (M) lesions were available from 30 patients with Stage II, III and IV CRC, and were subjected to immunohistochemical (IHC) staining for MMP-1. Both cytoplasmic expression in cancer cells (CC) and stromal (ST) expression were related to pertinent clinical and follow-up data. RESULTS: In a pairwise comparison of P-M pairs, CC expression (but not ST expression) in P and M was significantly different (Wilcoxon rank test, p=0.037). Strong CC expression in P was significantly related to the presence of lymph node involvement at diagnosis (p=0.008). CC expression in M was intense only in metachronous metastases (Stage II/III disease) but never in synchronous metastases (Stage IV) (p=0.034). There was a significant down-regulation of CC (p=0.004) in liver metastasis (n=9) in comparison with all other metastatic sites (n=21). ST expression in P (but not in M) showed a linear decrease in parallel with increasing stage (p=0.028 for linear trend). MMP-1 expression was not significantly associated with any other clinicopathological variables, including age, gender, carcinoembryonic antigen (CEA) or patients' disease-free or overall survival. CONCLUSIONS: These data suggest that MMP-1 may play an important role in tumour invasion and metastasis of CRC.     

Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment

Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A-based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE-/- mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A-treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1-dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM-1/PECAM-1-directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.     

Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine.

Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine.     

DNA methylation,smooth muscle cells,and atherogenesis

DNA methylation is a form of epigenetic modification of the genome that can regulate gene expression. Hypermethylation of CpG islands in the promoter areas leads to decreased gene expression, whereas promoters of actively transcribed genes remain nonmethylated. Because of cellular proliferation and monoclonality of at least some of the lesion cells, atherosclerotic lesions have been compared with benign vascular tumors.1,2 However, although genetic and epigenetic background favors neoplastic transformation, atherosclerotic plaques never develop to malignant tumors. Among cancer cells, common features are genome-wide hypomethylation, which correlates with transformation and tumor progression. Recent studies have shown that DNA methylation changes occur also during atherogenesis and may contribute to the lesion development.     

Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial

BACKGROUND: Many women using hormone replacement therapy (HRT) will discontinue HRT and lose its bone-protective effect. Methods to preserve bone density in these women need to be explored. This multicenter, international, randomized, blinded, 12-month study was conducted to assess the effect of alendronate sodium on bone density in women who had recently discontinued HRT. METHODS: The 144 postmenopausal women included in the study were diagnosed as having low bone mineral density (BMD) and had recently discontinued HRT. They were randomized to receive either a daily dose of 10 mg of alendronate sodium or matching placebo. The main outcome measures were spine, hip, and total body BMD; biochemical markers of bone turnover; and tolerability. RESULTS: Alendronate treatment was associated with a 2.3% mean increase (95% confidence interval [CI], 1.7%-3.0%) in spine BMD compared with a mean loss of 3.2% (95% CI, - 4.6% to - 1.7%) in patients receiving placebo, for a difference of 5.5% (95% CI, 4.2%-6.8%) between alendronate and placebo. Greater hip and total body BMD preservation was also observed with alendronate use. Bone turnover decreased significantly with alendronate (bone-specific alkaline phosphatase levels decreased by 20% and urinary N-telopeptide/creatinine ratio by 47%), but increased in the placebo group (by 18% and 36%, respectively). Alendronate was well tolerated, with no increase in adverse events compared with placebo. CONCLUSIONS: A high rate of bone loss was observed in the first 12 to 15 months after discontinuation of HRT in postmenopausal women with low BMD. Treatment with alendronate increased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRT in this population.     

Co-infection with Chlamydia pneumoniae and Helicobacter pylori results in vascular endothelial dysfunction and enhanced VCAM-1 expression in apoE-knockout mice

BACKGROUND: Upregulation of proinflammatory endothelial cell adhesion molecules and decreased bioactivity of endothelial nitric oxide (NO) are important in the pathogenesis of atherosclerosis. We investigated the effects of co-infection with Chlamydia pneumoniae and Helicobacter pylori on these two events in apoE-KO mice. METHODS: Thirty-two apoE-KO mice, 8 weeks old, were equally divided into 4 groups. The first 2 groups were infected with either C. pneumoniae or H. pylori, while the 3rd group was infected with both C. pneumoniae and H. pylori. Mice from the 4th group and 4 wild-type mice served as controls. Thoracic and abdominal aortas were harvested after 10 weeks, and staining for vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 was analyzed by immunocytochemistry. The endothelial vasomotor responses of thoracic aortas to methacholine were studied in organ chambers in the absence and presence of L-NAME. The plasma levels of nitrate/nitrite were measured. RESULTS: Staining for VCAM-1 was more intense at the branching sites of aortas from mice with co-infection than in mono-infected or noninfected apoE-KO mice. The relaxation responses to methacholine and the plasma levels of nitrate/nitrite were significantly less in the co-infected group than in the other groups (p < 0.05). CONCLUSION: Co-infection of apoE-KO mice with C. pneumoniae and H. pylori seems to be associated with impaired bioactivity of endothelial NO and increased expression of VCAM-1 at branching sites. The findings may suggest an additive interaction of these pathogens in atherogenesis.     

Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media.

BACKGROUND: Atherosclerosis begins early in life. Infections might contribute to the pathogenesis of atherosclerosis. In this study, we investigated whether acute infections in children could alter the carotid wall morphology and the lipid profile. METHODS: Mean carotid intima-media thickness (IMT) was measured by high-resolution ultrasound in 28 hospitalised children (mean age: 5+/-2 years), who fulfilled the diagnostic criteria of acute infections (body temperature, >38 degrees C; C-reactive protein, >15mg/ml, and clinical), and in 20 age- and gender-matched controls. Antibodies against oxidised low-density lipoprotein (anti-oxLDL antibodies), as well as total and high-density lipoprotein cholesterol (HDL-C) were analysed in all children. The infection group was investigated both during the acute illness and 3 months after clinical recovery (post-infection). RESULTS: During the acute illness, the infection group had elevated anti-oxLDL antibodies and decreased HDL-C, as compared to those obtained at 3 months and in controls (p<0.05). These changes in the infection group were followed, at 3 months, by thickening of carotid intima-media. Those who received antibiotics during their acute illness had less carotid thickening than those who were not treated with antibiotics (p<0.05). CONCLUSION: Acute infections in children seem to be accompanied by enhanced oxidative modification of LDL and by decrease in HDL-C. These lipid changes may be followed by thickening of carotid artery intima-media. These findings suggest that, in childhood, acute infections could be associated with increased risk of atherosclerosis, and warrant further studies on this topic.     

Pathogenesis of hereditary hemochromatosis: genetics and beyond

Hereditary hemochromatosis (HH) comprises several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and secondary tissue iron deposition. The most common form of this disorder is called HFE-related HH and is caused by homozygosity for the C282Y mutation in the HFE gene. Recently, other less common hereditary forms of iron overload have been recognized and are designated as non-HFE-related HH. The identification and cloning of HFE and other genes involved in iron metabolism has greatly expanded our understanding of many aspects of HH. The introduction of a commercially available genetic test for the C282Y and H63D mutations of HFE allows presymptomatic diagnosis, and adds precision to studies of the population genetics of HFE-related HH. It is now recognized that a substantial proportion of C282Y homozygotes does not develop clinically significant iron overload, and modifier genes may be involved in this phenomenon. Mouse models of HH and cell culture studies have increased our understanding of the normal physiology and pathophysiology of iron homeostasis. Future investigations will refine our knowledge of the mechanisms of action of HFE protein, the phenotypic variability observed in persons homozygous for the C282Y mutation, and the mechanisms responsible for non-HFE-related HH.