Vitamin D analogs: novel therapeutic agents for cardiovascular disease?

Vitamin D3 plays a key role in regulating calcium and mineral homeostasis in support of normal development and maintenance of bone. The classic effects of vitamin D3 include promoting absorption of dietary calcium in the gut and, through its actions as a steroid endocrine hormone, regulating the synthesis and secretion of parathyroid hormone. The effects of the vitamin D3 system are mediated through the highly regulated generation of the potent, active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D3 exerts its effects through the vitamin D3 receptor (VDR), a ligand-activated nuclear receptor expressed in a wide array of tissue and cell types. Studies performed in mice rendered deficient for VDR suggest that calcitriol and VDR may inhibit the renin-angiotensin system and reduce blood pressure in the long-term. Clinical studies suggest that administration of vitamin D3 analogs produces differential benefit with regards to mortality in dialysis patients; other studies suggest that vitamin D3 analogs may provide cardiovascular benefit in both dialysis and nondialysis patients. This paper reviews clinical and preclinical studies, which suggest that vitamin D3 analogs may provide therapeutic utility in the treatment of cardiovascular disease independent of those mechanisms typically associated with the vitamin D3 endocrine system.     

Adhesion molecules in cardiovascular disease: opportunities for new therapeutic directions?

Adhesion molecules mediate the adhesion of leukocytes and platelets to the endothelium by specific interactions with precisely defined ligands. Increased levels of adhesion molecules and/or their ligands are found on activated endothelial cells, eg, in allograft rejection, leading to the possibility that inhibition of this process may result in reduced transendothelial migration by leukocytes. Related structures on the surface of the platelet are responsible for the activation of the cell that results in aggregation and possible thrombus formation. Inhibition of these processes may be effected by monoclonal antibodies, low molecular weight polysaccharides, or by peptides. If this approach is successful, then a new class of therapeutic agent may become available.     

Toll-like receptor modulation in cardiovascular disease: a target for intervention?

Toll-like receptors (TLRs) form a family of pattern recognition receptors that have emerged as key mediators of innate immunity. These receptors sense invading microbes and initiate the immune response. TLR-mediated inflammation is an important pathogenic link between innate immunity and a diverse panel of clinical disorders. Among the processes in which TLRs play a role are cardiovascular disorders such as cardiac ischaemia, coronary artery disease, ventricular remodelling, cancer angiogenesis or transplant rejection. From these, many important opportunities for disease modification through TLR signalling manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated and this article reviews the current status of these treatment strategies for cardiovascular disease.     

Anti-oxidants-- a protective role in cardiovascular disease?

Established risk factors for cardiovascular disease (CVD), such as hypertension, smoking and diabetes mellitus, explain only some of the observed variation in clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of CVD. All of these risk factors are associated with increased oxidative stress in the vessel wall, which may contribute to CVD by several mechanisms. Studies in animal models of CVD have suggested that natural and synthetic anti-oxidants can prevent the development of clinical end points. These observations have generated the hypothesis that anti-oxidant therapy might also prevent CVD in human populations. This has been supported by epidemiological studies showing a negative correlation between circulating concentrations or dietary intake of natural anti-oxidant vitamins and CVD event rate. Many studies have also demonstrated a beneficial effect of anti-oxidants on surrogate markers of CVD such as endothelial function and lipoprotein oxidation. However, the results of large prospective randomised controlled intervention trials, mostly involving vitamin E in patients at increased risk of CVD, have been disappointing and have failed to demonstrate the anticipated benefits. This paper will critically examine the evidence and try to offer some explanation for the apparent failure of animal and epidemiological data to translate into meaningful clinical benefits.     

Oxcarbazepine for epilepsy--a useful new choice?

Oxcarbazepine* (Trileptal-Novartis), an anti-epileptic first marketed in the UK in 2000, is licensed for use both as adjunctive (add-on) therapy and as monotherapy for adults and children aged 6 years or over with partial-onset epileptic seizures, with or without secondary generalisation. The company claims that oxcarbazepine has "comparable efficacy" to carbamazepine with "greater tolerability", and causes "fewer withdrawals due to side effects compared to most established antiepileptic drugs". Here we discuss the place of oxcarbazepine in the treatment of epilepsy.     

Investigational Notch and Hedgehog inhibitors – therapies for cardiovascular disease

Introduction: During the past decade, a variety of Notch and Hedgehog pathway inhibitors have been developed for the treatment of several cancers. An emerging paradigm suggests that these same gene regulatory networks are often recapitulated in the context of cardiovascular disease and may now offer an attractive target for therapeutic intervention.

Areas covered: This article briefly reviews the profile of Notch and Hedgehog inhibitors that have reached the preclinic and clinic for cancer treatment and discusses the clinical issues surrounding targeted use of these inhibitors in the treatment of vascular disorders.

Expert opinion: Preclinical and clinical data using pan-Notch inhibitors (γ-secretase inhibitors) and selective antibodies to preferentially target notch receptors and ligands have proven successful but concerns remain over normal organ homeostasis and significant pathology in multiple organs. By contrast, the Hedgehog-based drug pipeline is rich with more than a dozen Smoothened (SMO) inhibitors at various stages of development. Overall, refined strategies will be necessary to harness these pathways safely as a powerful tool to disrupt angiogenesis and vascular proliferative phenomena without causing prohibitive side effects already seen with cancer models and patients.     

Drugs with anticholinergic properties: a potential risk factor for psychosis onset in Alzheimer's disease?

Psychosis in Alzheimer's disease is common and troublesome. The impact on the quality of life of both patients and caregivers is high and drug treatments raise concern in terms of both efficacy and safety. Therefore, identifying the risk factors that play an important role in the onset of psychosis is mandatory for the prevention of this clinical condition. From a biological point of view, drugs with anticholinergic properties are a reasonable cause of psychosis. Demented patients have been found to use a disproportionate amount of drugs with anticholinergic properties. On the other hand, new evidence suggests that the cholinergic system may be implicated not only with the onset of cognitive impairment, but even in the genesis of psychosis symptoms. This review focuses on biological and clinical data which suggest that anti-cholinergic drugs should be regarded as a potential risk factor for psychosis in Alzheimer's disease.     

Calcium-activated potassium channels – a therapeutic target for modulating nitric oxide in cardiovascular disease?

Importance of the field: Cardiovascular risk factors are often associated with endothelial dysfunction, which is also prognostic for occurrence of cardiovascular events. Endothelial dysfunction is reflected by blunted vasodilatation and reduced nitric oxide (NO) bioavailability. Endothelium-dependent vasodilatation is mediated by NO, prostacyclin, and an endothelium-derived hyperpolarising factor (EDHF), and involves small (SK) and intermediate (IK) conductance Ca²⁺-activated K⁺ channels. Therefore, SK and IK channels may be drug targets for the treatment of endothelial dysfunction in cardiovascular disease.

Areas covered in this review: SK and IK channels are involved in EDHF-type vasodilatation, but recent studies suggest that these channels are also involved in the regulation of NO bioavailability. Here we review how SK and IK channels may regulate NO bioavailability.

What the reader will gain: Opening of SK and IK channels is associated with EDHF-type vasodilatation, but, through increased endothelial cell Ca²⁺ influx, l-arginine uptake, and decreased ROS production, it may also lead to increased NO bioavailability and endothelium-dependent vasodilatation.

Take home message: Opening of SK and IK channels can increase both EDHF and NO-mediated vasodilatation. Therefore, openers of SK and IK channels may have the potential of improving endothelial cell function in cardiovascular disease.     

Antisense technology for the prevention or the treatment of cardiovascular disease: the next blockbuster?

Antisense technology might be a gateway to the treatment of diseases by targeting the expression of genes rather than permanently altering them. Thus, there will be fewer ethical concerns. Antisense oligonucleotides (ASO) can alter target gene expression by binding to RNA. Once bound, the ASO either disables or induces the degradation of the target RNA. This technology may be used to treat various conditions (including cancer, diabetes, and hypertension, as well as autoimmune and cardiovascular diseases). ASOs are potentially potent, selective and well-tolerated drugs. Mipomersen (ISIS 301012) inhibits human apolipoprotein (apo)B-100 synthesis and lowers circulating apoB and low-density lipoprotein cholesterol levels. ASO technology may provide a spectrum of agents targeting other vascular risk factors or mediators of atherosclerosis.     

Omega-3 fatty acids and HDL. How do they work in the prevention of cardiovascular disease?

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) from marine origin have been strongly associated with cardiovascular protection, even at low doses ( < 1g/d). Despite the research performed in this promising area, basic aspects, such as the ideal doses and the mechanisms by which ω-3 PUFAs act, are not precisely defined. The best known biological property of ω-3 PUFAs is their hypotriglyceridemic effect, but other cardioprotective actions, such as reduction of arrhythmia susceptibility, antithrombotic, antiinflammatory and antioxidant effects, improvement of endothelial function, and delayed atherosclerosis development have received an increased interest in recent years. Some of these actions are also ascribable to high-density lipoproteins (HDL). Abundant epidemiological evidence links increasing HDL-cholesterol concentrations to cardiovascular protection. Recently, the protein cargo (proteome) of HDL particles has been attributed a key role in their functionality. In this review, we summarize the main effects of ω-3 PUFAs on HDL-cholesterol, HDL subfractions, and its main proteins, apolipoproteins (apo) AI and AII. The shared cardioprotective actions of ω-3 PUFAs and HDL are reviewed as well.     

An inflammatory pathomechanism for Parkinson's disease?

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), striatal dopamine deficiency and appearance of Lewy bodies. Inflammatory and immune, or even autoimmune, stigmata, have been described in post-mortem brains of PD patients. Although disputed in humans, a reactive astrocytosis and a lymphocytic infiltration in the SNpc have been observed in animal models of PD, which need further examination. This review summarizes the current knowledge on brain inflammation in humans with PD, and how inflammation and/or (auto)immune reactions within the SNpc could be linked to other pathophysiological mechanisms that have been hypothesized for the etiology of PD, such as oxidative stress, exposure to neurotoxins, and post-infectious or post-traumatic injuries. In particular, we discuss how microglial cells could be activated during the course of PD, and present a new hypothesis that PD-linked protein (alpha-synuclein, in particular) aggregates could be implicated in their activation, to induce a chronic and sustained inflammation involved in the progression, at least, of the disease. The current status of anti-inflammatory agents, either already tried in PD clinical trials or putatively usefull as adjuvant therapies for PD, is also discussed.     

MicroRNA: Potential Targets for the Development of Novel Drugs?

MicroRNA (miRNA) is an endogenous non-protein coding small RNA molecule that negatively regulates gene expression by the degradation of messenger RNA (mRNA) or the suppression of mRNA translation. miRNA plays important roles in physiologic processes such as cellular development, differentiation, proliferation, apoptosis, and stem cell self-renewal. Studies show that deregulation of miRNA expression is closely associated with tumorigenicity, invasion, and metastasis. The functionality of aberrant miRNAs in cancer could act either as oncogenes or tumor suppressors during tumor initiation and progression. Similar to protein-coding gene regulation, dysregulation of miRNAs may be related to changes in miRNA gene copy numbers, epigenetic modulation, polymorphisms, or biogenesis modifications. Elucidation of the miRNA expression profiles (miRNomes) of many types of cancers is starting to decode the regulatory network of miRNA-mRNA interactions from a systems biology perspective. Experimental evidence demonstrates that modulation of specific miRNA alterations in cancer cells using miRNA replacement or anti-miRNA technologies can restore miRNA activities and repair gene regulatory networks affecting apoptotic signaling pathways or drug sensitivity, and improve the outcome of treatment. Numerous animal studies for miRNA-based therapy offer the hope of targeting miRNAs as an alternative cancer treatment. Developing the small molecules to interfere with miRNAs could be of great pharmaceutical interest in the future.     

Is RGS-2 a new drug development target in cardiovascular disease?

Hypertension is the most common cardiovascular disease. The regulator of G-protein signalling (RGS) proteins modify the activity of G proteins, and mice deficient in RGS-2 are hypertensive. On vascular smooth muscle, RGS-2 is involved in cross-talk between the nitric oxide (NO)-relaxation pathway and thrombin-contraction pathway. RGS-2 binds to the cGMP-dependent protein kinase I-alpha from the NO relaxation pathway to terminate protease-activated receptor-1 signalling. It has been suggested that RGS-2 is a new drug development target for hypertension. Mice deficient in RGS-2 also have impaired antiviral immunity. It is difficult to envisage how RGS-2 could be targeted to have effects on the cardiovascular system without affecting immunity. Also, it is not clear whether or not targeting RGS-2 will have advantages over targeting receptors. Only an increased understanding of the physiological and pathological role of RGS-2 will help us resolve these issues.