Cardiovascular & Haematological Disorders - Drug Targets - Volume 12, Issue 2, 2012

Epidemiological studies have demonstrated that diets rich in fruits and vegetables can prevent or delay the onset of many chronic diseases including cardiovascular disease (CVD). While more current research has begun to focus on the effects of specific polyphenol compounds found in fruits and vegetables, mechanistic insights have been hampered by the multiple simultaneous effects these compounds may have on the disease process. In this article, we review the basic research studies that have evaluated the effects of citrus flavonoids to: improve dyslipidemia, normalize glucose homeostasis, prevent oxidative stress, and attenuate inflammation, which collectively have the ability to enhance metabolic health and improve CVD risk.

Apolipoprotein B48 (apoB48)-containing triglyceride-rich lipoproteins are atherogenic and therefore it is important to understand factors that regulate their metabolism in the intestine. Insulin resistant states are associated with increased intestinal output of apo B48, but the mechanistic studies explaining this overproduction have relied heavily on models of diet-induced insulin resistance. There is evidence that glucagon-like peptide (GLP) secretion is diminished in insulin resistant and diabetic states, which may have implications for postprandial lipid secretion. This review presents a survey of studies on GLPs and intestinal lipoprotein metabolism, along with some insights into the net physiological significance of GLP action in postprandial lipoprotein metabolism. Studies with GLP-1 receptor agonists and dipeptidyl peptidase-IV inhibitors have indicated that GLP-1 in pharmacological and physiological doses can inhibit intestinal TRL production. On the other hand, GLP-2 has an acute stimulatory effect on intestinal apoB48 secretion. Modulating GLP action may serve as a strategy to improve postprandial dyslipidemia in insulin resistant states.

Atherosclerosis is a multi-factorial inflammatory disease with accumulation of lipids and recruitment of leukocytes into the subendothelial space. Due to the consistent inflammation in vessels, a subset of atherosclerotic plaques is even prone to physical disruption or producing thrombosis that triggers acute coronary syndromes (ACS). Cyclooxygenase (COX) and the downstream diverse prostanoids are involved in numerous physiological activities and inflammatory processes. Remarkably, prostanoids are a group of bioactive lipid mediators, and play a series of complicated and even contradictory roles during the progression of atherogenesis. Some, mainly prostacyclin (PGI2) have cardioprotective effects to inhibit the aggravation of atherosclerosis, however, others including prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), increase the risk of cardiovascular thromboembolic events. Therefore, the controversial effects bring about a debate on the use of cyclooxygenase-2 (COX-2) specific and non-specific inhibitors in the prevention from cardiovascular diseases. In addition to reverse cholesterol transport (RCT), high-density lipoprotein (HDL) exerts several beneficial effects on endothelial protection. Moreover, HDL could also regulate the expression of COX-2 and the production of PGI2 in endothelial cells. While as a diverse complex of heterogeneous particle composed of various apolipoproteins, enzymes and lipids, the individual components of HDL, such as apolipoprotein A-I (apoA-I) and sphingosine-1-phosphate (S1P), have distinct effects on COX-2 expression and PGI2 production in endothelial cells. In the present review, we summarize the roles of COX-2 as well as PGI2 in atherosclerosis and atherothrombosis, the controversial vascular effects on prostanoid inhibition by COX-2 inhibitors, and the effects of HDL on the endothelial protection by the upregulation of COX-2 and the release of PGI2 during the progression of atherosclerosis.

The prevalence of diabetes has been rapidly increasing in world-wide countries. The dominant cause of mortality in diabetic patients is cardiovascular complications. Mechanism for the susceptibility of diabetic patients to cardiovascular disorders remains unclear. Elevated oxidative stress was detected in diabetic patients or in animal models. Mitochondria are one of major sources of reactive oxygen species (ROS) in cells. Mitochondrial dysfunction and DNA mutations have been detected in diabetic patients. Diabetes-associated metabolic disorders, including hyperglycemia, hypertriglyceridemia, hypercholesterolemia, hypoalphalipoproteinemia, and increased levels of advanced glycation end products, glycated and oxidized lipoproteins, are associated with oxidative stress. Glycated or oxidized low density lipoproteins (LDL) impair the activities of mitochondrial respiratory chain complex enzymes in vascular endothelial cells (EC). Dysfunction in mitochondrial respiration may increase the formation of ROS in mitochondria. NADPH oxidase (NOX) generates ROS in cytosol. Increased NOX activity was detected in diabetic patients. Glycated and oxidized LDL increase the expression of NOX and ROS production in EC. Diabetes-associated metabolic disorders may lead to mitochondrial dysfunction, NOX activation and excess ROS production, which results in oxidative stress and promotes cardiovascular disorders in diabetic patients. Statins, metformin and anthocyanidins may help to attenuate oxidative stress in vasculature induced by diabetes-associated metabolic disorders.

Obesity is increasing in people of Chinese background whether in China or in other countries. The purpose of this review is to discuss the associations of obesity in men and women of Chinese background with cardio-metabolic risk with specific attention to body fat distribution. Evidence suggests that current BMI and WC targets may actually underestimate the cardio-metabolic risk in Chinese compared to European populations from which they were derived. Through a number of investigations, we and others have identified that Chinese men and women tend to have higher cardio-metabolic risk factors at a given body size than people of European background (from which guidelines are generally derived). Our additional investigations have indicated that Chinese men and women have greater amounts of VAT, but similar amounts of DSAT at a given body fat than Europeans and it may be the higher VAT in Chinese people that is, in part, responsible for the greater cardio-metabolic risk in the Chinese. Further investigation of this topic should prove fruitful in shedding light onto the determinants of body fat accumulation and distribution that may help to inform obesity prevention and treatment strategies.

SM22α is a shape change and transformation sensitive 22 kDa actin-binding protein of the calponin family. It is ubiquitous to vascular and visceral smooth muscle, and is an early marker of smooth muscle differentiation. It is also present in fibroblasts, and some epithelium. SM22α may be involved in calcium-independent smooth muscle contraction. Recent evidence suggests that disruption of SM22α induces vascular inflammation and is involved in osteochondrogenesis in arterial diseases. This is consistent with activation of NF-κB signaling, where NF-κB activity is upregulated in vascular injury. High expression of SM22α inhibits cell proliferation in VSMCs and in injured arteries. SM22α acts as a tumor suppressor. Loss of its expression is an early event in cell transformation and the development of some tumors, coinciding with cellular plasticity.

Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. After being released into the circulation, platelets play key roles in the surveillance of vascular injury, and can quickly adhere and aggregate at the site of injury, which are critical events for vascular repair and hemostasis. However, the same biological processes of platelet adhesion and aggregation may also cause thrombotic disorders. The formation of a platelet plug at sites of atherosclerotic lesion rupture is the most common mechanism leading to myocardial or cerebral infarction. Platelet-related deep vein thrombosis is also one of the leading causes of mortality worldwide. The contribution of several platelet receptors and their ligands has been highlighted in these processes. In platelet adhesion, particularly at high shear stress, GPIbα-von Willebrand factor (VWF) interaction may initiate this event, which is followed by GPVI signalling and firm platelet adhesion mediated by members of the integrin family, such as β3 (αIIbβ3) and β1 (α2β1, α5β1) integrins. In platelet aggregation, although GPIbα-VWF, P selectin-sulfatides, and other molecules, may be involved, the process is mainly mediated by β3 (αIIbβ3) integrin and its ligands, such as fibrinogen and VWF. It is intriguing that platelet adhesion and aggregation still occur in mice lacking both fibrinogen and VWF, suggesting that other unforeseen molecule(s) may also be important in these processes. Identification and characterization of these molecules will enrich our knowledge in the basic science of hemostasis and thrombosis, and may lead to the development of new therapies against bleeding disorders and thrombotic diseases.

Apolipoprotein (apo) C-III is a small protein (79 amino acids) and a component of triacylglycerol (TAG)-rich very low density lipoproteins (VLDL) and high density lipoproteins. We have unraveled a new intracellular role of apoCIII in promoting hepatic VLDL1 (Sf > 100) assembly/secretion under lipid-rich conditions. Feeding apoc3-null mice with a high fat diet for two weeks or palm oil gavage failed to stimulate VLDL1 production in vivo. Reconstitution of apoC-III expression using adenovirus encoding human apoC-III resulted in robust production of VLDL1 containing apoB-100 or apoB-48. The stimulatory effect of human apoC-III on the assembly and secretion of VLDL1 was recapitulated ex vivo in McA-RH7777 cells cultured in lipid-rich media. Metabolic labeling experiments showed that apoC-III plays a central role in (i) the formation of lumenal lipid droplets (LLD) rich in TAG, and (ii) promoting bulk TAG incorporation during VLDL1 assembly. Structure-function analysis of naturally occurring apoC-III variants (Ala23Thr and Lys58Glu) defined two functional domains that play respective roles in LLD formation and VLDL1 assembly. Unraveling the intracellular role of apoC-III in the atherogenic TAG-rich VLDL1 production provides new insights into the strong influence of the APOA5-A4-C3-A1 gene locus on plasma TAG concentrations and premature atherosclerosis.

ATPase-dependent chromatin remodeling complex encompasses a group of evolutionarily conserved proteins that utilize energy derived from ATP hydrolysis to drive nucleosome movement contributing to transcriptional regulation. Brahma-related gene 1 (Brg1) and Brahma (Brm) are the core components of the mammalian remodeling complex. The past decade has witnessed a great expansion in our knowledge regarding the role of Brg1 and Brm in modulating the function of the cardiovascular system (CVS) under both physiological conditions and disease states owing much to the availability of tissue-specific Brg1/Brm-null animals. This review summarizes the current proceedings on how Brg1 and Brm contribute to the morphogenesis within the CVS and importantly, how Brg1 and Brm maintain the homeostasis of adult organisms, the disruption of which bears clear implications in the pathogenesis of such cardiovascular diseases as atherosclerosis and cardiac hypertrophy.