Current Pharmaceutical Design - Volume 16, Issue 37, 2010

Heart disease remains the leading cause of death in the United States and the main cause of heart disease is coronary artery disease [1]. This Special Issue on New Perspectives in Cardiovascular Medicine presents a series of reviews on potential new therapeutic targets for both vascular and cardiac pathologies. Unsurprisingly, given the powerful cardioprotective influence of endothelial cells, many of the reviews focus on targets located on this innermost layer of the vascular tree. The review by Fu and Zhu [2] examines the potential role of endothelial ectopic adenosine triphosphate synthase which is located in the endothelial cell plasma membrane and produces ATP which can bind to purinoceptors activating signalling pathways which regulate endothelial function. The capabilities of this protein structure range from the recruitment of inflammatory cells to the endothelium thus inducing vascular inflammation, to acting as a receptor for apolipoprotein A-1, implying a role for cholesterol metabolism, to the inhibition of prostacyclin synthesis and the enhancement of nitric oxide bioactivity. These capabilities render the molecule a strong target for atherosclerosis, hypertension and lipid disorders. Lumsden et al. [3] review the role of C-type natriuretic peptide, the paracrine element of the natriuretic peptide axis which plays such a fundamental role in cardiovascular homeostasis by modulating fluid and electrolyte balance and vascular tone. C-NP is produced by both endothelial and cardiac cells and Lumsden et al describe both its physiological and pathological roles in vascular and cardiac function exemplified by its control of blood flow in resistance vasculature and of pacemaker current in the heart as well as by its ability to protect against myocardial ischemic reperfusion injury. The authors thus suggest that pharmacological manipulation of the C-NP receptors, NPR-B and -C, hold promise in the advancement of treatment of cardiovascular disease such as heart failure, atherosclerosis and pulmonary hypertension. Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase. The review by Arrigoni et al. [4] again focuses on manipulating endothelial function in cardiovascular pathologies, this time through the effects of both cellular and circulating ADMA on both nitric oxide dependent and independent pathways. The review further describes the role of dimethylarginine dimethylaminohydrolase (DDAH) in the metabolism of ADMA and a means by which the levels of ADMA can be modulated therapeutically to benefit such cardiovascular pathologies as hypertension, metabolic syndrome and diabetes. In the review on cytoprotection by natural and synthetic polyphenols by Jiang et al. [5], the authors discuss the therapeutic benefits of these molecules against myocardial injury following ischemia reperfusion. They describe that these cardiprotective effects have been attributed to anti-oxidant activities, preservation of nitric oxide, anti-inflammatory activities and modulation of matrix metalloproteinases as well as such novel mechanisms as the modulation of the function of enzymes involved in epigenetic modifications such as histone acetyltransferases. In addition, polyphenols may also be of therapeutic benefit against the development of cardiac hypertrophy, ventricular remodeling and fibrosis after myocardial infarction. Inflammation plays a fundamental role in atherosclerosis associated cardiovascular disease and adhesion of immune cells has a critical role in the inflammatory response and indeed the pathophysiology of this disorder. P-selectin is an inflammatory adhesion molecule which enables the recruitment of leukocytes to the endothelium and to activated platelets involved with the growing thrombus. It is thought to be critical in the progression of atherosclerosis and leukocyte recruitment to the plaque. The review by Woollard and Chin-Dusting [6] suggests that the targeting of P-selectin is a strong clinical candidate for developing novel therapeutic strategies in inflammatory diseases including atherosclerosis. Hagemeyer and Peter's review [7] on targeting platelet integrin GPIIb/IIIa revisits the critical role of this molecule in thrombus formation. Here the authors review current knowledge on GPIIb/IIa structure, signalling pathways and receptor function. Importantly, the positives and limitations of current anti-thrombotic compounds are also studied in detail with the view to learning from the successes and failures of GPIIb/IIIa blocker development towards making new and better improved blockers. Raising high density lipoproteins (HDL) is the focus of the review by Murphy et al. [8] which explores the complexities of such a task and why this potentially exciting therapeutic indication is still in its infancy with regards current understanding of the HDL metabolic pathway and all the implications thereof. The review comprehensively describes current and future HDL-raising medications and details the benefits and limitations of these. The review [9] by the late Sir James Black and his close collaborator and friend, Fitzgerald fittingly closes this Special Issues on New Perspectives in Cardiovascular Medicine - many of the contributors of whom are world-renowned in the respective fields. Sir James and Fitzgerald track through the historic detail in the discovery of the β-adrenoceptors and adrenergic system and focuses on its application in patients with congestive heart failure. Key to the review is that the different properties of β-blockers show the undesirability of β2- adrenoceptor activation and thus the rationale for the use of selective β2-adrenoceptor blockers is discussed. Together these reviews comprehensively illustrate the wealth of novel cardiovascular therapeutic targets for the better management of cardiovascular disease.

Adenosine triphosphate (ATP) synthase produces ATP in cells and is found on the inner membrane of mitochondria or the cell plasma membrane (ectopic ATP synthase). Here, we summarize the functions of ectopic ATP synthase in vascular endothelial cells (ECs). Ectopic ATP synthase is involved in adenosine metabolism on the cell surface through its ATP generation or hydrolysis activity. The ATP/ADP generated by the enzyme on the plasma membrane can bind to P2X/P2Y receptors and activate the related signalling pathways to regulate endothelial function. The β-chain of ectopic ATP synthase on the EC surface can recruit inflammatory cells and activate cytotoxic activity to damage ECs and induce vascular inflammation. Angiostatin and other angiogenesis inhibitors can have antiangiogenic functions by inhibiting ectopic ATP synthase on ECs. Moreover, ectopic ATP synthase on ECs is a receptor for apoA-I, the acceptor of cholesterol efflux, which implies that endothelial ectopic ATP synthase is involved in cholesterol metabolism. Coupling factor 6 (CF6), a part of ectopic ATP synthase, is released from ECs and can inhibit prostacyclin synthesis and promote nitric oxide (NO) degradation to enhance NO bioactivity. Because ATP/ADP generated by ectopic ATP synthase can induce NO production, substances such as CF6 can inhibit NO generation by inhibiting surface ATP/ADP production. Thus, the components of ectopic ATP synthase are associated with regulation of vascular tone. Through these functions, ectopic ATP synthase on ECs is considered a potential and novel therapeutic target for atherosclerosis, hypertension and lipid disorders.

Natriuretic peptides play a fundamental role in cardiovascular homeostasis by modulation of fluid and electrolyte balance and vascular tone. C-type natriuretic peptide (CNP) represents the paracrine element of the natriuretic peptide axis which complements the endocrine actions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). CNP is produced by the endothelium and the heart and appears to play a prominent role in vascular and cardiac function, both physiologically and pathologically. This provides a rationale for the therapeutic potential of pharmacological interventions targeted to CNP signalling. This article provides an overview of the biology and pharmacology of CNP, with emphasis on the cardiovascular system, and discusses pathologies in which drugs designed to manipulate CNP signalling maybe of clinical benefit.

Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase and consequently may have adverse effects on physiology, in particular in the cardiovascular system. This review highlights the mechanisms involved in the synthesis and metabolism of ADMA and their role in the control of nitric oxide (NO) synthesis. We describe how the effects of both cellular and circulating ADMA can alter physiological function involving both NO dependent and independent pathways and go on to describe how the metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH) is the major endogenous mechanism by which ADMA levels are regulated. Furthermore, we discuss the association of ADMA concentrations with cardiovascular disease and how ADMA levels can be modulated therapeutically by altering its production and/or metabolism. Finally we discuss the effects of some of the current pharmaceutical therapies used to treat cardiovascular disease and their involvement in the modulation of the ADMA/DDAH pathway.

While many naturally occurring polyphenols have been shown to have therapeutic benefits against myocardial injury following ischemia-reperfusion in various experimental models, our studies have demonstrated that synthetic flavonoids may also have potent cardiac cytoprotective actions. Together with the results reported in the literature, we suggest that synthetic polyphenols may be an ideal replacement for natural compounds in the development of myocardial protective drugs. Polyphenols exert myocardial protective effects via antioxidant activities, preservation of nitric oxide, antiinflammatory activities and modulation of matrix metalloproteinases. Recent studies have identified some novel mechanisms that may also contribute to polyphenol-induced myocardial protection, including prevention of mitochondrial dysfunction, pharmacological preconditioning, and modulation of the function of enzymes involved in epigenetic modifications such as histone acetyltransferases. In addition to the protective effects against acute myocardial injury, there has been experimental evidence showing that polyphenols may also modulate the development of cardiac hypertrophy, ventricular remodeling and fibrosis after myocardial infarction.

Inflammation plays a fundamental role in many chronic diseases, including atherosclerosis associated cardiovascular disease. Adhesion of immune cells plays a critical role in the inflammatory response and indeed the pathophysiology of inflammatory related diseases. P-selectin is an inflammatory adhesion molecule, enabling the recruitment of leukocytes to the endothelium and to activated platelets involved in the growing thrombus. P-selectin is critical in the progression of atherosclerosis as evidenced by knockout animal models where P-selectin knockout mice crossed with apoE deficient mice exhibit significantly reduced atherosclerosis and leukocyte recruitment in the plaque. A soluble form of P-selectin also exists, which may have pro-atherogenic and pro-thrombotic effects. Thus targeting of P- selectin remains a strong clinical candidate for developing novel therapeutic strategies in inflammatory diseases. This review will discuss the role of P-selectin and describe the function of P-selectin antagonists as clinical targets.

The platelet integrin GPIIb/IIIa plays an essential role in thrombus formation through interactions with adhesive ligands and has emerged as a primary target for the development of anti-thrombotic agents. Receptor activation is under strict control, with activators, inhibitors, and signalling mechanisms controlling its conformation. Structural biology research has produced high-resolution images defining the ligand binding site at the atomic level. Successful blockade of this ligand binding has validated GPIIb/IIIa as a therapeutic target in cardiovascular medicine. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet agents and have been used effectively in a wide variety of clinical scenarios including unstable angina, myocardial infarction, and high risk percutaneous coronary interventions with and without intracoronary stenting. Three inhibitors (abciximab, eptifibatide, and tirofiban) are currently licensed for human use. Surprisingly, oral GPIIb/IIIa antagonists have not been successful and there is an unmet need for effective anti-GPIIb/IIIa drugs that cause less bleeding problems and that can be orally applied. Here we review our current knowledge about GPIIb/IIIa structure, signalling pathways and receptor function, the benefits and limitations of current GPIIb/IIIa blockers and we take a look forward how the lessons learned from the mixture of success and failure of GPIIb/IIIa blocker development can be transformed in new and better GPIIb/IIIa blockers.

Cardiovascular disease remains the leading cause of morbidity and mortality globally. The disease is largely controlled with interventions managing atherogenic lipids including LDL and triglycerides. However a number of studies have shown that increasing HDL levels is likely to provide better outcomes for patients suffering from this disease. There has been an extensive research effort into understanding how HDL levels are regulated in the body and which pathways can be targeted therapeutically. The HDL metabolic pathway is however overwhelmingly complex. This has provided only limited success in trialing drugs designed to raise HDL. To add to the complexity HDL itself is a heterogeneous population of particles and there is controversy surrounding which HDL particle is the most cardio-protective. In addition there are varying opinions on which of the HDL cellular receptors are more important in humans (as opposed to what has been discovered in mice) in regulating these effects. In this article we explore the evidence for and against using the currently suggested methods of raising HDL and provide some evidence for how the adverse effects of these drugs could be corrected.

This review describes the clinical application of β-adrenergic blocking drugs over time in patients with congestive heart failure. The different pharmacological properties of these drugs in relation to clinical outcomes raise questions as to their optimal desirable profile based on studies showing the undesirable effects of excessive β2-AR activation. The rationale for the use of selective β2-AR antagonists in heart failure is discussed.