Cardiovascular expression profiling

Shiffman D et al. Gene expression profiling of cardiovascular disease models. Curr Opin Biotechnol 2000 11 598-601. 

Some of the gene expression profiling analysis biochips on the market include Affymetrix s standardized GeneChip for a variety of human and yeast genes and HyX Gene Discovery Modules for genes from tissues of the cardiovascular and from tissues that are germ infected. 

Archacki S, Wang Q. Expression profiling of cardiovascular disease. Hum Genomics 2004 1(5) 355—370. 

A recent study has provided insight into the association of ambient air pollution with increased cardiovascular morbidity and mortality. In this study, when human microvascular endothelial cells were exposed to a combination of ultrafine diesel exhaust particles and oxidized lipid components, a synergistic effect on the expression profiles of several gene modules that correspond to pathways relevant to inflammatory pathways such as atherosclerosis was observedJ57l The implications of this study include a greatly increased risk of heart disease in those with high cholesterol who breathe polluted air. 

Handley-Goldstone HM, Grow MW, Stegeman JJ (2005) Cardiovascular gene expression profiles of dioxin exposure in zebrafish embryos. Toxicol Sci 85 683-693 Hansen JM (2006) Oxidative stress as a mechanism of teratogenesis. Birth Defects Res Part C Embryo Today Rev 78 293-307... 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

It is important to note that an elevated and/or altered plasma lipid level is only one of a wide range of risk factors that contribute to the clinical manifestations of cardiovascular disease in humans (Lusis, 2000). Consequently, in some studies, the reduced incidence of atherosclerosis in animals fed CLA was not accompanied by an improvement in the plasma lipid profile during the CLA feeding phase (Wilson et al, 2000). Reasons for these effects are not understood fully. However, atherosclerosis can also be considered as a chronic inflammatory disease (Libby, 2002) and several important anti-inflammatory effects have been associated with the use of RA these include a reduction in the expression of COX-2, PGE2, reduced release of nitric oxide, a decreased production of pro-inflammatory cytokines, and PPARy activation (Urquhart et al, 2002 Yu et al, 2002 Toomey et al, 2003). 

The observed effects in cardiovascular disease modek can be rationalized by a local increase of bradyldnin and a local decrease of Ang II levek in affected tissues, but more detailed investigations on the biological and pharmacological mechanism have to be carried out. The absence of enzyme expression in the vasculature and the acidic pH optimum of proteolytic enzyme activity might be beneficial in terms of a clinical safety profile for CatA inhibitors. However, the most obvious challenge right now will be the clinical validation of thk novel target in humans by the demonstration of safety and efficacy. 

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