Progression Of Atherothrombotic Disease Research Articles

PREVENTION OF CORONARY HEART DISEASE

Primary prevention, based on healthy lifestyle habits that prevent the emergence of risk factors, is the preferred method of reducing cardiovascular risk. Reducing the prevalence of obesity is the most urgent task, and it is pleiotropic in that it affects blood pressure, lipid profile, glucose metabolism, inflammation, progression of atherothrombotic disease. Physical activity also improves several risk factors, with the added potential to lower heart rate.

Neutrophil gelatinase-associated lipocalin as a risk marker in cardiovascular disease.

Neutrophil gelatinase-associated lipocalin (NGAL) is a promising diagnostic biomarker of early acute kidney injury. Increasing evidence suggests that NGAL may also be involved in inflammatory processes in cardiovascular disease. NGAL modulates the enzymatic activity of matrix metalloproteinase-9 (MMP-9), which is an important mediator of plaque instability in atherosclerosis. The complex formation between NGAL and MMP-9 therefore suggests that NGAL might play a role in progression of atherothrombotic disease. This review summarises current data on NGAL in atherosclerosis, acute myocardial infarction, and heart failure.

From intraplaque haemorrhages to plaque vulnerability

Intraplaque hemorrhages are mainly related to inward neoangiogenesis, initiated from the adventitia by lipid-dependent outwardly convected signals, and by the immaturity of these neovessels, allowing leaks and hemorrhages. Repeated intraplaque hemorrhages play a major role in the evolution of thrombotic occlusive disease, similar to the role of intraluminal thrombus in the progression of abdominal aortic aneurysm toward rupture. Red blood cells (RBCs) are an important source of unesterified cholesterol, because their membranes are particularly cholesterol rich. This unesterified cholesterol is rapidly organized in cholesterol crystals, highly toxic for cell and membranes. Oxidized cholesterol and LDL provoke the irreversible covalent aggregation of proteins, including hemoglobin, forming ceroids, which are also highly toxic. Hemoglobin play a major role of prooxydant molecules in this context, by its ability to release heme and iron, the main catalyser of oxidative reaction. In the context of type 2 diabetes, the oxidative potential of intraplaque-free hemoglobin play a predominant role in the progression of atherothrombotic disease toward clinical expression. Associated to RBC, intraplaque hemorrhages convey leukocyte, mainly neutrophils in human, and plasma zymogen that are the main source of proteases, including coagulation proteases, activation of the fibrinolytique system, release of leukocyte serine proteases and cathepsins and activation of MMPs. These proteases concentrate in the hemorrhagic/necrotic core rendered plaque highly vulnerable. An adaptive immune response takes place in the adventitia, in regard of hemorrhagic plaques, in relation to outwardly convected oxidized or proteolyzed neoantigens, and chemokinic signals. Finally, intraplaque hemorrhages and thrombi are the site of weak pathogen entrapment, which promote all these oxydative and proteolytic phenomenons.

Quest for Genes Regulating Plasma Fibrinogen Concentration

Identification of the genes and genetic variants that confer proneness to coronary heart disease (CHD) remains an outstanding challenge to the biomedical research community. A host of genes are likely to contribute, yet only a small fraction have so far been unequivocally identified. This is not least because of the limited increase in risk contributed by each susceptibility gene. Thus, in most instances, more than one gene aberration will be required (heritability is polygenic), and clinical disease results from multifaceted interactions between susceptibility genes and environmental factors. Heritability is also heterogeneous; ie, different constellations of susceptibility genes are involved in different individuals. Adding to the complexity is epistasis or gene–gene interactions, where interactions among loci result in the genetic effects at one locus differing in magnitude or direction as a consequence of the genotype at another locus.1 See page 1287 One of the preferred molecular genetic approaches is to focus on the dissection of measurable quantitative traits that are associated with disease susceptibility in epidemiological studies. This is generally considered to be a more practicable strategy than to target affection status itself, the latter end point being even more complex, further distant from gene function, and statistically less informative. One example of an intermediate trait that translates variation at the gene level into variation in the risk of CHD is the measure of plasma fibrinogen concentration. The plasma fibrinogen concentration is an established risk factor for CHD,2 and several pathophysiological mechanisms have been identified, linking plasma fibrinogen to the development and progression of atherothrombotic disease.3 The fibrinogen molecule comprises 2 symmetrically …

Homocysteine metabolism in renal failure

Of the many amino acid abnormalities that are present in chronic renal failure, hyperhomocysteinemia has drawn increasing attention because of its proposed role in the development and/or progression of atherothrombotic disease. Renal function is a major determinant of fasting plasma homocysteine level, and the inverse relationship between the glomerular filtration rate (GFR) and plasma homocysteine level is present throughout the whole range of renal function. Although this suggests an active renal homocysteine metabolism, no important urinary excretion or active homocysteine extraction has been demonstrated in the human kidney. Analysis of plasma concentrations of the various cofactors and substrates of homocysteine metabolism, and the effects of different therapies indicate that an abnormal folate metabolism may be the cause of hyperhomocysteinemia in uremia. This is further supported by the finding that homocysteine remethylation, as assessed by stable isotope techniques, is impaired in dialysis patients. It is unclear whether decreased remethylation is also responsible for other abnormalities of homocysteine metabolism in renal failure such as the exaggerated rise and the impaired decline of plasma homocysteine concentration after methionine or homocysteine loading. More studies are necessary to pinpoint the precise mechanisms that lead to hyperhomocysteinemia in renal failure. This should lead to optimal treatment and, ultimately, to the prevention of cardiovascular complications in this vulnerable patient group.

Homocysteine-Induced Endoplasmic Reticulum Stress and Growth Arrest Leads to Specific Changes in Gene Expression in Human Vascular Endothelial Cells

Alterations in the cellular redox potential by homocysteine promote endothelial cell (EC) dysfunction, an early event in the progression of atherothrombotic disease. In this study, we demonstrate that homocysteine causes endoplasmic reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells (HUVEC). To determine if these effects reflect specific changes in gene expression, cDNA microarrays were screened using radiolabeled cDNA probes generated from mRNA derived from HUVEC, cultured in the absence or presence of homocysteine. Good correlation was observed between expression profiles determined by this method and by Northern blotting. Consistent with its adverse effects on the ER, homocysteine alters the expression of genes sensitive to ER stress (ie, GADD45, GADD153, ATF-4, YY1). Several other genes observed to be differentially expressed by homocysteine are known to mediate cell growth and differentiation (ie, GADD45, GADD153, Id-1, cyclin D1, FRA-2), a finding that supports the observation that homocysteine causes a dose-dependent decrease in DNA synthesis in HUVEC. Additional gene profiles also show that homocysteine decreases cellular antioxidant potential (glutathione peroxidase, NKEF-B PAG, superoxide dismutase, clusterin), which could potentially enhance the cytotoxic effects of agents or conditions known to cause oxidative damage. These results successfully demonstrate the use of cDNA microarrays in identifying homocysteine-respondent genes and indicate that homocysteine-induced ER stress and growth arrest reflect specific changes in gene expression in human vascular EC.