Cardiovascular & Haematological Disorders - Drug Targets - Volume 14, Issue 2, 2014

In this issue of Cardiovascular & Hematological Disorders – Drug Targets, eight review articles are published with a common theme of Atherosclerosis, Heart Disease and Diabetes. The surge of metabolic syndromes in the past 2-3 decades, characterized by central obesity, hypertension, fasting hyperglycemia, and diabetic dyslipidemia, is associated with increasing incidence of heart diseases and vascular complications. Clinically, prevention and treatment of metabolic syndromes and related cardiovascular abnormalities necessitates a comprehensive understanding of alterations in cellular and molecular events at transcriptional, post-transcriptional, and post-translational levels. The eight review articles published in this issue cover research frontiers in the areas of histone methylation, cardiolipin metabolism, collagen homeostasis, energy utilization, cholesterol movement, and lipoprotein production during the pathogenesis of cardiovascular complications and diabetic dyslipidemia. Histone methylation represents an epigenetic mechanism underlying the pathophysiology of atherogenesis, hyperglycemia, hypoxia, vascular inflammation, and cardiovascular diseases, such as congestive heart failure, dilated cardiomyopathy, and thoracic aortic aneurysm. Xu and Fang have presented compelling experimental evidence, obtained from cell culture and genetically modified animal models, that changes in histone methylation occur in cardiomyocytes and vasculature, composed of vascular smooth muscle cells and endothelial cells. The authors foresee the development of new high-throughput technologies enabling a comprehensive, genome-wide profiling of histone methylations between normal and diseased cardiovascular systems. Human congestive heart failure develops in association with hypertension, hyperinsulinemia, and diabetes. Hatch and coworkers have reviewed the metabolism of cardiolipin, particularly tetralinoleoyl-cardiolipin, in the heart and the pathology of the Barth Syndrome (BTHS) associated with deficiency of cardiolipin remodeling (i.e. transacylation) catalyzed by the BTHS gene product tafazzin. The authors thus envisage that defining the mechanistic relationship, between acyl-chain composition of cardiolipin, mitochondrial failure, and cardiomyopathy, may reveal new potential therapeutic targets for the prevention and treatment of heart failure and cardiac dysfunction. Another aspect of heart failure is the development of cardiac fibrosis, characterized by abnormal deposition of type I and type III collagens. Roche and Czubryt have provided an overview of the current knowledge on transcriptional regulation of type I collagen expression. The authors stressed the need for future investigations into the regulatory mechanisms (both transcriptional and post-transcriptional/post-translational) that govern collagen homeostasis in different cell types in cardiac tissue. A better characterization of fibrosis development at cellular and molecular levels will yield a better understanding of other symptoms associated with metabolic disorders, such as fibrosis in nonalcoholic steatohepatitis. From energy metabolism point of view, a switch from glucose utilization to fatty acid utilization by heart occurs under diabetic conditions. The source of fatty acids is derived from (i) unsuppressed lipolysis in adipose tissue and (ii) hydrolysis of plasma triglyceride-rich lipoproteins, such as very low-density lipoproteins (VLDL), catalyzed by lipoprotein lipase (LPL). Rodrigues and co-workers reviewed experimental evidence for a concerted regulation of expression, transmigration, and presentation of cardiac LPL on the endothelium surface in the coronary lumen. The augmented fatty acid utilization by cardiomyocytes may constitute a cardiac protective mechanism during the early stages of hyperglycemia. Fasting and postprandial dyslipidemia is a common feature of metabolic syndrome. Pharmaceutical means for the treatment of dyslipidemia is aiming at reducing low density lipoprotein (LDL)-cholesterol and boosting high density lipoprotein (HDL)- cholesterol. Adeli and co-workers presented a comprehensive overview on the current status of the use of dipeptidyl peptidase- 4 (DPP-4) inhibitors and the glucagon-like peptide-1 receptor (GLP-1R) agonists as potential therapy for dyslipidemia, in addition to its known effect in treating hyperglycemia (as GLP-1 is a potent insulin secretagogue). An additional complication in diabetic dyslipidemia is alterations in HDL structure and HDL composition, which apparently exert a negative impact on the presumed anti-atherogenic function of HDL. Zheng and co-workers examined the impact of changes in both HDL-protein (e.g. glycation of apoA-I) and HDL-lipids (e.g. elevation in triglyceride and sphingosine-1- phosphate) on endothelium function under diabetic conditions, and explored the potential protective action of these changes at early stage of hyperglycemia. Along the same line of HDL metabolism, Zhang and co-workers reviewed current understanding concerning HDL biogenesis, emphasizing the requirement of ABCA1 and ABCG1 for apoA-I-containing HDL formation, and the potential role of caveolin-1 in the process. In addition, Qin and co-workers presented experimental evidence suggesting a possible involvement of phospholipid transfer protein (PLTP), a protein known to play a role in HDL remodeling, in the process of diabetes and obesity development. The eight topics presented in this issue are selected from panel presentations at The Second Canada-China Symposium on Atherothrombosis, Diabetes and Obesity held at Simon Fraser University Harbour Centre on July 20-21, 2013. Ascardiovascular and metabolic diseases are becoming prevalent in both West and East demographics, the international science community welcomes a strong participation of Chinese investigators joining the workforce in unraveling genetic and environmental factors contributing to the pathogenesis of these debilitating chronic diseases.

Cardiovascular disease (CVD) represents a major health risk to the global population. In disease settings, cells that constitute the vasculature undergo profound changes both morphologically and functionally paralleling alterations in gene expression profile. At the transcriptional level, gene expression is steered by the epigenetic machinery including DNA methyltransferases, histone variants, non-coding regulatory RNAs, chromatin remodeling complexes, and histone modifying enzymes. The N-terminal tails of histones, primarily histones H3 and H4, are post-translationally modified creating a unique platform for transcriptional regulation. This review summarizes our current understanding of the role of histone methylation in modulating the vascular transcriptome and its relevance in CVD with an outlook on future directions.

Cardiolipin is a major membrane phospholipid in the mitochondria and is essential for cellular energy metabolism mediated through mitochondrial oxidative phosphorylation. Recent studies indicate that it plays a diverse role in cellular metabolism. Eukaryotic cardiolipin is synthesized de novo from phosphatidic acid via the cytidine-5’-diphosphate- 1,2-diacyl-sn-glycerol pathway and is deacylated to monolysocardiolipin in order for it to be remodelled into the form that is observed in mitochondrial membranes. This resynthesis of deacylated cardiolipin from monolysocardiolipin occurs via the Barth Syndrome gene product tafazzin and acyllysocardiolipin acyltransferase-1, monolysocardiolipin acyltransferase- 1 and the alpha subunit of trifunctional protein. Heart failure is a disease condition in which the amount and type of cardiolipin is altered. Several animal models have been generated to study the role of altered cardiolipin in heart failure. In many of these models loss of the tetralinoleoyl-cardiolipin species is observed during the development of the heart failure. In the doxycycline inducible short hairpin RNA tafazzin knock down mouse, loss of tetralinoleoyl-cardiolipin is associated with a mitochondrial bioenergetic disruption. Reduction in mitochondrial supercomplex formation and NADH dehydrogenase activity within these supercomplexes is observed. Modulation of CL fatty acyl composition may serve as a therapeutic strategy for the treatment of several pathologies including cardiac dysfunction.We propose that increasing cardiolipin may improve mitochondrial function and potentially serve as a therapy for diseases which exhibit mitochondrial dysfunction involving reduced cardiolipin.

Cardiac fibrosis is the pathological remodeling of the extracellular matrix (ECM) in response to stresses such as pressure overload or injury [1]. While initially adaptive, myocardial remodeling and subsequent fibrosis causes increased wall stiffness, arrhythmias, cardiac dysfunction, and eventually heart failure [2]. Though the disease processes and origins may differ, excess deposition of fibrillar collagens type I and III characterizes fibrosis in the heart, lungs, kidneys, liver, and skin. Under normal physiological conditions, high tensile strength collagen fibers maintain cardiac structural integrity, connect individual cardiomyocytes, transmit contractile force, and resist deformation and rupture of the ventricle during systole [1]. Various factors contribute to the development of fibrosis by altering expression of ECM genes, including increased synthesis of pro-inflammatory cytokines, alterations in the levels of circulating hormones, and mechanical strain resulting from ECM degradation. This review focuses on the transcriptional mechanisms governing expression of the major cardiac collagen, type I. Key cis- and trans-acting regulators of collagen I gene expression are discussed. Surprisingly, relatively few transcriptional regulators of collagen synthesis have been identified specifically in cardiac fibroblasts. However, key players have been identified in other tissue and cell types, and are important to consider in elucidating the molecular mechanisms underpinning collagen gene expression in the heart in both health and disease.

The earliest change that occurs in the diabetic heart is reduced glucose consumption, with a switch to utilization of fatty acids (FA) predominantly as an energy resource. Although this adaptation might be beneficial in the short-term, over a protracted duration, it is potentially catastrophic given the malicious effects produced by high FA in cardiomyocytes. In this review, we describe how the endothelial cell (EC), a “first-responder” to hyperglycemia, communicates with the underlying cardiomyocyte. As this cross-talk is expected to facilitate increased FA delivery to, and utilization by, the cardiomyocyte, understanding this conversationshould assist in devising new therapeutic strategies to prevent or delay diabetic heart disease.

Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia – an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver.

Type 2 diabetes mellitus (T2DM) is accompanied by dysfunctional high-density lipoprotein (HDL) and this is characterized by alterations in its composition and structure compared with HDL from normal subjects (N-HDL). HDL from diabetic subjects (D-HDL) has a diminished endothelial protective capacity including reducted ability to exert antioxidative activity, stimulate endothelial cell (EC) production of nitric oxide (NO) and endothelium-dependent vasomotion, promote endothelial progenitor cell (EPC)-mediated endothelial repair. In addition, D-HDL promotes EC proliferation, migration and adhesion to the matrix. The present review provides an overview of these effects of diabetic HDL on EC function, as well as the possible changes of D-HDL structure and composition which may be responsible for the diminished endothelial protective capacity of D-HDL.

Atherosclerosis is one major cause of cardiovascular diseases, the leading cause of death in industrialized countries. Reverse cholesterol transport (RCT) is thought to be one primary pathway to protect against atherosclerosis. The first and rate-limiting step of RCT is ATP-binding cassette transport A1 (ABCA1) and ABCG1-mediated cholesterol efflux from the cells. Recently, caveolin-1 (CAV1), a scaffolding protein that organizes and concentrates certain caveolininteracting signaling molecules and receptors within caveolae membranes, has been shown to regulate ABCA1 and ABCG1-mediated cholesterol efflux probably via interacting with them. In the present review, we summarize the current knowledge and views on the regulatory role of CAV1 on the cholesterol homeostasis with emphasis on the association of CAV1 with ABCA1 and ABCG1. We conclude that the dominance of the positive regulation by CAV1 on the ABCA1 and ABCG1-mediated cholesterol efflux is depending on the species, cell types, as well as the levels of CAV1 expression.

It has been reported that phospholipid transfer protein (PLTP) is an independent risk factor for human coronary artery disease. And metabolic tissues are important contributors to the systemic pools of PLTP protein. Consistently, PLTP mass and activity have been found to be elevated in the plasma of type 2 diabetes mellitus (T2DM) and obese patients. In this review, we summarized the recent progresses made in the PLTP research field and focused on the complexity of the implication of PLTP in obesity, insulin resistance and T2DM.

Cardiovascular disease remains a major cause of morbidity and mortality in developed countries. New treatments, in the form of novel oral anticoagulants (NOAC) that reduce thrombotic risk are now available for patients with atrial fibrillation (AF) or acute coronary syndrome (ACS). Warfarin has been the cornerstone of thromboprophylaxis in patients with AF, but treatment is cumbersome, inconvenient and often unreliable, with fluctuating time in therapeutic range. Thrombotic events also continue to occur in a significant number of ACS patients despite antiplatelet therapy. Thus there is an unfilled need to reduce thrombotic events in ACS and AF patients. NOAC comprise direct factor Xa inhibitors (apixaban, rivaroxaban, darexaban, edoxaban), direct thrombin inhibitors (dabigatran) and PAR-1 antagonists (vorapaxar, atopaxar). In this review, we compare and contrast NOACs and review their individual and specific clinical trial database in ACS and AF. In the setting of ACS, the role of NOAC is unclear, as any reduction in ischemic events appears to be offset by hemorrhagic risk. However, NOAC have a definite place in the treatment of patients with non-valvular AF, where they are at least as effective, if not superior to warfarin.