The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: II. Therapeutic management of atherogenic dyslipidemia.

J Clin Hypertens (Greenwich). 2009;11:520-527. (c)2009 Wiley Periodicals, Inc.Strategies for the effective management of cardiovascular risk factors in patients with the metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM) are essential to help reduce cardiovascular morbidity and mortality. Treatment strategies should be multifactorial and include the promotion of therapeutic lifestyle changes, as well as pharmacologic therapies to treat individual risk factors according to current guidelines. In an accompanying article, the importance of atherogenic dyslipidemia as a risk factor for the development of cardiovascular disease in patients with MS or T2DM was highlighted. Current treatment options for managing this characteristic form of atherogenic dyslipidemia are limited and tend to be only moderately effective. The focus of this review is the current pharmacotherapies available for the management of atherogenic dyslipidemia in patients with the MS or T2DM, highlighting the rationale for combining available treatments. Novel strategies currently in clinical development are also discussed.

The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: Part I. Increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus.

Both the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) confer an increased risk of coronary heart disease and cardiovascular disease (CVD). As MS and T2DM become more prevalent, there will be an associated rise in the number of individuals with or at risk for CVD and its related disorders. One major underlying cause of CVD in patients with MS or T2DM is a characteristic form of atherogenic dyslipidemia. This article reviews the evidence that demonstrates that individuals with MS or T2DM are at increased risk for CVD and highlights atherogenic dyslipidemia as an important risk factor for the development of CVD in these individuals. In an accompanying article, current pharmacotherapies available for the management of atherogenic dyslipidemia in individuals with MS or T2DM are discussed.

Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2alpha under oxidative stress.

Chronic hepatitis C is often associated with oxidative stress. Hepatitis C virus (HCV) utilizes an internal ribosome entry site (IRES) element for translation, in contrast to cap-dependent translation of the majority of cellular proteins. To understand how virus translation is modulated under oxidative stress, HCV IRES-mediated translation was compared with cap-dependent translation using a bicistronic reporter construct and hydrogen peroxide (H2O2) as a stress inducer. In H2O2-sensitive HeLa cells, H2O2 repressed translation in a time- and dose-dependent manner, concomitant with the kinetics of eIF2alpha phosphorylation. A phosphomimetic of eIF2alpha, which mimics the structure of the phosphorylated eIF2alpha, was sufficient to repress translation in the absence of H2O2. In H2O2-resistant HepG2 cells, H2O2 activated both HCV IRES-mediated and cap-dependent translation, associated with an increased level of phospho-eIF2alpha. It was postulated that H2O2 might stimulate translation in HepG2 cells via an eIF2alpha-independent mechanism, whereas the simultaneous phosphorylation of eIF2alpha repressed part of the translational activities. Indeed, the translational repression was released in the presence of a non-phosphorylatable mutant, eIF2alpha-SA, resulting in further enhancement of both translational activities after exposure to H2O2. In HuH7 cells, which exhibited an intermediate level of sensitivity towards H2O2, both HCV IRES-mediated and cap-dependent translational activities were upregulated after treatment with various doses of H2O2, but the highest level of induction was achieved with a low level of H2O2, which may represent the physiological level of H2O2. At this level, the HCV IRES-mediated translation was preferentially upregulated compared with cap-dependent translation.