Cardiovascular & Haematological Disorders - Drug Targets - Volume 7, Issue 2, 2007

INTRODUCTION/SYNOPSIS OF THE SPECIAL ISSUE: Cardiovascular Risk Factors and Metabolic Syndrome in Cardiovascular Diseases Cardiovascular disease is the leading cause of morbidity and mortality in the world and is on an alarming rise in Asian Chinese populations. Risk factors are commonly associated with the dietary habit and lifestyle in the population such as fat consumption, smoking, and also factors including hypertension, hyperlipidemia, which are particularly common in subjects with metabolic syndrome and diabetes. With reference to recommendations focusing on reducing dietary saturated fat, in Asia, however, the problem may not be eating excessive meat but an over intake of calories leading to abdominal obesity, insulin resistance, diabetes, hypertension and the metabolic syndrome. Additionally, the prevalence of the disease grows partly because of the rising numbers in the elderly populations worldwide, particularly noticeable in the Asia. In the first part of this special thematic issue, Cheung and Thomas review the literature and recent studies focusing on the profile of the risk factors in Asian Chinese populations. These are followed by reviews by Thomas and his colleagues and Tan, respectively, on the dietary intervention and the management of dyslipidaemia in the metabolic syndrome. It is shown that a healthy diet early on in life may prevent the development of cardiovascular disease; even in those who already have clinically overt cardiovascular disease. The reviews also highlight on the roles of therapeutic lifestyle modification and drug therapies. Cardiovascular Protection: Approaches to Prevent and Treat Cardiovascular Diseases Cellular and molecular activities induced by cardiovascular stress are the major local events for the protective/compensatory responses or else for the pathogenesis. The second part of this issue aims at reviewing some of the recently-identified mechanisms relevant to the agents and targets proposed for cardiovascular protection. Metabolic nuclear receptors are a group of nuclear hormone receptor transcription factors and play important roles in lipid metabolism, tissue inflammation and remodeling. These receptors such as the peroxisome proliferator-activated receptors have been shown to be involved in pathogenesis of atherosclerosis and ligands for some of the receptors are effective in treating patients with disorders associated with metabolic syndrome. In addition, recent evidence reviewed by Wang suggests modulation of the metabolic nuclear receptors could have potential therapeutic values in treating obesity, hypertension and albuminuria. Moreover, there are circulating substances that can confer cardiovascular protection. Sex hormones are among those agents, which have been shown to have beneficial effects on heart and vessels. Interestingly, in addition to the female hormones, recent literature reviewed by Wong suggests that testosterone can exert a good degree of cardioprotective actions. Intriguingly, the level of testosterone declines in the aging group, which is closely correlated to a rising trend of cardiovascular risk in the elderly male population. Another approach is to target factors known to be involved in the pathogenesis of cardiovascular diseases so as to protect the cardiovascular functions in adverse conditions. Novel targets recently identified are highlighted in this thematic review for extrapolating the therapeutic values of the targets. Experimental studies have demonstrated that ATP-binding cassete transporter-1 (ABCA1) is involved in lipid transportation from cells to apolipoprotein and in cholesterol homeostasis and atherogenic events. Recent evidence reviewed by Zhu suggests oxidized LDL can lower the level of ABCA1, contributing to endothelial dysfunction and plaque formation. Moreover, lesions in the microvessels associated with hyperglycemia that can contribute to the pathogenesis of atherosclerosis by oxidative stress and formation of glycation end product.

The metabolic syndrome is a constellation of vascular disease risk factors that includes hyperglycaemia, hypertension, and dyslipidaemia, which are largely mediated by accumulating fat depots, particularly when centrally deposited. Increasing adiposity promotes insulin resistance, low grade inflammation and endothelial dysfunction, which promote the development of atherogenic vascular disease. Increases in percentage body fat result from a number of parameters, including ageing, and changes in lifestyle factors that promote a metabolic imbalance, such as decreasing physical activity and adverse dietary patterns. As Asian populations continue to modernize, levels of physical activity are declining as home and workplace jobs become more automated and sedentary and transportation more readily available. Similarly, dietary changes are introduced, with healthy traditional plant-based diets being replaced by cheaper calorie dense high fat foods. These changes are resulting in rapid increases in the prevalence of obesity throughout Asia, and the subsequent development of the metabolic syndrome. To minimise further development of the obesity pandemic and subsequent vascular disease, innovative population-based preventative lifestyle and therapeutic strategies interventions need to be introduced.

Most dietary recommendations are based on studies of limited power and do not adequately reflect the current knowledge base, particularly with regard to effects of diet on clinical outcomes, the most important endpoint from the patients' perspective. In this review we discuses the current state of dietary research, and present a summary of the evidence upon which to base dietary recommendations and guidelines for atherosclerotic vascular disease prevention. We also highlight the complexity and limitations of interpreting current diet-based epidemiological studies in isolation.

The metabolic syndrome consists of a clustering of metabolic derangements that cause the affected individual to have an increased risk for developing cardiovascular disease. Dyslipidemia is an important component of the metabolic syndrome and is included in all the definitions of the metabolic syndrome published by different international committees to identify individuals with the metabolic syndrome. Atherogenic dyslipidemia in the metabolic syndrome comprises of hypertriglyceridemia, low levels of high-density lipoprotein cholesterol and a preponderance of small dense low-density lipoprotein particles. The pathogenesis of dyslipidemia in the metabolic syndrome will be reviewed and the roles of therapeutic lifestyle modification and drug therapies in the treatment of dyslipidemia will be discussed.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) belongs to a family of ligand-activated nuclear receptor and transcription factors. The essential roles of PPAR-γ in controlling metabolic processes have been underscored by the successful use of PPAR-γ agonists thiazolidinediones to treat insulin resistance, a central feature of metabolic syndrome. PPAR-γ is also expressed in the vascular tissues including endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages. Increasing evidence suggests that PPAR-γ is implicated both in the maintenance of vascular homeostasis and in the pathogenesis of a number of vascular conditions such as atherosclerosis, hypertension and restenosis. As an important regulator of vascular biology, PPAR-γ may represent a potential therapeutic target for these metabolic vascular disorders. This review will focus on the recent advances related to the biological functions of PPAR-γ in various vascular processes as well as the significances of the pharmacological activators/modulators of this metabolic nuclear receptor in vascular disorders.

Male gender is a risk factor for cardiovascular diseases. Testosterone being the main male sex hormone is therefore believed to be responsible for the deleterious effect of the male. However, there are recent studies showing that testosterone level is lower in patients with ischemic heart diseases, and testosterone treatment alleviates the symptoms. Earlier studies showed that functional androgen receptors are present in the heart and that testosterone acts directly at the myocardium. There is increasing evidence to suggest testosterone confers cardioprotection by direct action on the myocardium. Here, we review the recent literature on association between testosterone and myocardial ischemia in males, and the signal transduction mechanisms that mediate the action of testosterone in the heart. The studies reviewed in this article provide evidence that testosterone may confer protection via a varieties of mechanisms, which may be both genomic and non-genomic. Further studies are warranted to further delineate the integration of signaling mechanisms and to explore the possibility of using testosterone in the aging male population with ischemic heart diseases.

Vascular endothelial dysfunction is considered an initial step of atherogenesis, and the complicated cellular events of atherosclerosis begin with focal inflammation leading to foam cell formation and accumulation of cholesterol in the subendothelial space. Of the cells that make up atherosclerotic plaque, vascular endothelial cells (ECs) are the most resistant to cholesterol accumulation. However, ECs express receptors for modified lipoproteins and have the biochemical pathways for sterol synthesis and receptor-mediated endocytosis of lipoproteins. Cholesterol efflux continues even when cellular cholesterol mass is unchanged. Therefore, cholesterol efflux pathways may play an important role in endothelial cholesterol homeostasis. Recent study results suggest that apolipoprotein A-I and high density lipoproteins promote cellular cholesterol efflux through mechanisms depending on ATP-binding cassette transporter A1 in ECs. Caveolae and its structural protein caveolin-1 are abundant in ECs and could be contributors to cholesterol trafficking as well. However, the roles of each pathway in efflux and homeostasis of cellular cholesterol in ECs are still controversial. This article reviews recent progress in the understanding of cholesterol efflux and underlying mechanisms in ECs and proposes a model of efflux of cellular cholesterol. Such a cholesterol efflux pathway could provide insight into the efficient removal of excess cellular cholesterol in preventing atherogenesis.

Our review aims to examine the cellular and molecular mechanisms of cardiovascular protection of green tea polyphenols, particularly epigallocatechin gallate (EGCG), which focuses on the anti-oxidative and anti-inflammatory effects. EGCG is the major and the most active component in green tea. Studies have shown that EGCG protects cellular damage by inhibiting DNA damage and oxidation of LDL. One of the protective properties of EGCG is its ability to scavenge free radicals. EGCG can also reduce the inflammatory response associated with local tissue injuries such as the hepatocellular necrosis in acute liver injury induced by carbon tetrachloride. The protective effect of EGCG is due to its ability to decrease lipid peroxidation, oxidative stress and the production of nitric oxide (NO) radicals by inhibiting the expression of iNOS. EGCG also ameliorates the overproduction of pro-inflammatory cytokines and mediators, reduces the activity of NF-κB and AP-1 and the subsequent formation of peroxynitrite with NO and reactive oxygen species. Thus, EGCG effectively mitigates cellular damage by lowering the inflammatory reaction and reducing the lipid peroxidation and NO generated radicals leading to the oxidative stress. Green tea is proposed to be a dietary supplement in the prevention of cardiovascular diseases in which oxidative stress and proinflammation are the principal causes.

Cardiovascular diseases remain the leading cause of mortality and morbidity worldwide. Despite substantial improvements in acute management, survivors of myocardial infarction often progress to heart failure. Since adult cardiomyocytes (CMs) do not regenerate, their loss permanently compromises myocardial contractile function. Heart transplantation is currently the last resort for end-stage heart failure, but is hampered by a severe shortage of donor organs and rejection. Cell-based therapies are a promising alternative: Various cell types such as human fetal CMs, skeletal muscle myoblasts and smooth muscle cells have been tested but these approaches are also limited by cell availability or side effects ( e.g. due to their non-cardiac identity). In recent years, clinical studies exploiting adult bone marrow mesenchymal stem cells for transplantation in patients with coronary artery disease have reported favorable outcomes but their cardiomyogenic ability is limited. By contrast, human embryonic stem cells (hESCs), derived from the inner cell mass of blastocyst- stage embryos, are pluripotent and can self-renew and differentiate into all cell types including CMs. Furthermore, hESC-derived CMs (hESC-CMs) are viable human heart cells that can functionally integrate with the recipient organ after transplantation. This article reviews the current state and hurdles of hESC-CM research, as well as their therapeutic potentials and limitations.