Current Drug Targets - Volume 16, Issue 4, 2015

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NFkB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

Research investigations on adipose tissue were focused for several decades on its “storage” function. Emerging evidence unveiled adipose tissue as an endocrine organ releasing a several mediators termed as adipokines. Adipokine-mediated functions include both physiological and pathophysiological roles such as regulation of energy metabolism, immune response and vascular homeostasis, as well as inflammatory and metabolic diseases (i.e. atherogenesis, diabetes and obesity clustered in the concept of metabolic syndrome). A dysregulation of adipokine levels has been also suggested as a potential common mechanism underlying these disorders. For instance, an unbalance between pro- and anti-inflammatory adipokines was positively associated with traditional risk factors (dyslipidaemia, hypertension, insulin resistance) in obesity, diabetes and atherogenesis. Adipokine-mediated activities particularly affected endothelial dysfunction/activation and intraplaque inflammation/vulnerability. The purpose of this narrative review is to provide an overview on the role of adipokines in atherogenesis. Evidence from basic research studies about adipokine-induced regulation of vascular and immune cell subsets will be discussed. Finally, conflicting results from clinical trials we be reported, with an attempt to better understand the reason why promising basic research results did not allow a speedy “into human” translation for clinical management of atherogenesis.

Atherosclerosis is the main pathophysiological process underlying acute cardiovascular diseases. Life-threatening conditions, such as myocardial infarction and ischemic stroke, are provoked by the sudden rupture of vulnerable atherosclerotic plaques, characterized by thin, highly inflamed and collagen-poor fibrous cap. Whereas both innate and adaptive inflammation progressively emerged as driving force of this processes, less is known about the involvement of neutrophils (PMNs). Advances in laboratory techniques during the last two decades disclosed that PMNs play a crucial role in promoting plaque vulnerability by the release of different enzymes, such as gelatinases (matrix metalloproteinases) collagenases, elastase and myeloperoxidase. Accordingly, circulating levels of PMNs and their products have been investigated as potential markers of plaque instability in both primary and secondary prevention on cardiovascular diseases. In addition, the development of different classes of drugs targeting PMNs activation is emerging as an interesting field of research. This narrative review will provide an update on the role of PMNs in promoting plaque vulnerability also discussing the potential effects of therapeutic strategies targeting PMN on plaque vulnerability.

Atherosclerosis and its major acute complications, myocardial infarction and stroke, are the leading causes of death and morbidity worldwide. Despite major advances in cardiovascular intervention and healthcare, improving preventive care and treatment remains a continuous mission for cardiovascular research. Within the last 10 to 15 years, the endocannabinoid system has emerged as an important lipid signaling system involved in many biological processes. Growing evidence suggests that an overactive endocannabinoid-CB1 receptor signaling promotes the development of cardiovascular risk factors such as obesity, insulin resistance and dyslipidemia. This prompted an increasing interest in studying the role of the endocannabinoid system in atherosclerosis. As opposed to the detrimental actions of CB1 signaling, the endocannabinoid-CB2 receptor axis exhibits an anti-inflammatory and atheroprotective role. We will review recent findings from experimental and clinical studies aimed at understanding the complex actions of endocannabinoid signaling in cardiovascular disease. This is followed by an outlook on emerging targets for possible therapeutic intervention.

Atherosclerosis is a chronic inflammatory disease leading to cardiovascular diseases responsible for a high level of morbidity and mortality worldwide. Increasing evidence tends to hold that humoral and cellular immune responses are a key component of human atherosclerosis development. Since the last decade, auto-antibodies have been identified as active mediators of cardiovascular disease, some presenting protective effects whereas others act as proatherogenic factors. This review presents an overview of the most relevant auto-antibodies with regards to their respective cardiovascular prognostic value in acute coronary syndrome, stroke and other cardiomyopathies, and their potential pathophysiologic implication in atherogenesis. Insights in the mechanisms of action of auto-antibodies show that they commonly modulate the innate immune system towards a pro- or anti-inflammatory response and/or affect the regulation of basal heart rate. The increased understanding of the auto-antibodies functional properties has led to the development of new therapeutic approaches targeting the innate immune system or the epitope-binding site. Some of these auto-antibodies have been reported to be independent prognostic factors of poor disease outcome. In addition to conventional risk factors, these autoantibodies could be helpful biomarkers to increase the sensitivity and specificity of the cardiovascular stratification tools.

Sodium-hydrogen exchangers (NHEs) and aquaporins (AQPs) are key regulators of cell volume and intracellular ions both in physiological and pathological conditions. By directly affecting water and ion exchanges across the plasma membrane, NHEs and AQPs, particularly isoforms 1, can also influence vascular tone and the cytoskeleton, respectively, in response to several types of stimuli, such as hypertonic stress. NHE-1 and AQP1 are mainly expressed in tissues of the cardiovascular system. Their excessive activation in response to elevated extracellular osmolarity, as occurring in diabetic hyperglycemia, can be deleterious both for micro- and macrovascular endothelial cells. Although NHE-1 and AQP1 regulate the intracellular volume and ions, they also influence the activation of hypertonicity-responsive genes and cell functions involved in glucotoxicity and vascular injury. Because of the involvement of NHEs and AQPs in micro- and macrovascular disease, including arterial hypertension and atherosclerotic plaque destabilization, research has focused on developing inhibitors of these transporters. We here review current knowledge of NHEs and AQPs investigating biological aspects and mechanisms of their regulation, including their potential as target for developing new drugs that could target diabetic atherosclerosis.

The awareness that chronic kidney disease (CKD) is a condition of dramatically increased cardiovascular risk has prompted an intense research activity, aimed at identifying factors that are specifically involved in the development of cardiovascular complications of CKD and that can be delayed or reduced by novel pharmacological approaches. This may be the case with indoxyl sulfate (IS). IS is an endogenous molecule derived from indole, a product of protein metabolism by intestinal bacteria, which acts via the aryl hydrocarbon receptor (AhR). IS accumulates early in CKD and exerts proinflammatory and other detrimental effects on the cardiovascular system, in particular promoting atherosclerosis and atherosclerosis-related arterial remodeling. Furthermore, IS also contributes to renal damage, thereby fueling a vicious circle. Dialysis is poorly effective in removing IS, but its levels can be lowered by preventing the bacterial generation of indole or by absorbing this latter within the intestine. More intriguing, although still theoretical, is the possibility of inhibiting the action of IS at the cell level, by antagonizing the binding to AhR or IS intracellular signaling. Therefore, IS targeting might become an option for reducing the cardiovascular burden of CKD.

Atherosclerosis, the major risk factor for cardiovascular disease (CVD) and the leading cause of death worldwide, is a multifactorial chronic inflammatory disease, which, clinically manifests from early lipid-rich lesions to plaque rupture and/or thrombosis in the arterial wall. The myeloid cell compartment, including macrophages and dendritic cells (DCs), is long known to contribute to the initiation and progression of atherosclerosis. However their complex phenotypic heterogeneity hampers our full understanding of their role. Here, we review the biological and functional versatility of the myeloid cells in atherosclerosis. Several distinct subsets of macrophages and myeloid cells have been identified in atherosclerotic plaques, including subsets that are specific to atherosclerosis itself. Our ability to target them therapeutically is still limited. The challenge for the future will be the definition of treatments that target specific myeloid subsets to prevent the activation of pro-atherogenic myeloid cell subsets while preserving the anti-atherogenic and repairable function of myeloid cells.

In the last 20 years, microRNAs (miRNAs) have become the most promising class of diagnostic and prognostic biomarkers for human cancer. From a therapeutic perspective, advances in the understanding of the molecular role of miRNAs in the pathological processes have significantly influenced the selection of new therapeutic modalities. Moreover, the intrinsic characteristics that confer stability to miRNAs in vitro, allow a longer molecular/structural resistance and activity in vivo. Preclinical models have consistently underlined the feasibility and efficacy of miRNA-based therapies, either alone or in combination with current targeted therapies. The appealing strength of such therapeutic option dwells in miRNAs’ ability to concurrently target multiple genes, frequently in the context of a specific network/pathway. This property allows miRNA-based therapy to be extremely efficient in regulating distinct biological processes relevant to normal and pathological cell homeostasis. The purpose of this review is to summarize the role of miRNAs in gastrointestinal carcinogenesis and their potential use as novel biomarkers and therapeutics.

The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Almost all of these cell surface protein-protein interactions (PPIs) represent high-value therapeutic targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or cancers, and there are several biologics including antibodies and fusion proteins targeting them that are in various phases of clinical development. Small-molecule inhibitors or activators could represent possible alternatives if the difficulties related to the targeting of protein-protein interactions by small molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF, TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates.