Cardiovascular & Haematological Disorders - Drug Targets - Volume 8, Issue 3, 2008

Extensive investigations have implicated cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL) -1, and IL-6 as contributing to the pathology of ischemia-reperfusion (I/R) injury, since an increase in the production of those cytokines was clinically detected after myocardial infarction and cardiopulmonary bypass surgery. Current evidence indicates that these cytokines are autocrine contributors to myocardial dysfunction and cardiomyocyte necrosis in I/R injury, whereas, earlier evidence also suggest that cytokines have controversial roles in cardiovascular pathophysiology. Accordingly, it becomes vital to better define the mechanisms of action of cytokines as important steps towards the development of effective therapeutic strategies to combat their deleterious effects in ischemia-induced myocardial injury. Since TNF-α, TGF-β1, IL-1, IL-6 and IL-8 have been frequently studied in cardiovascular diseases, especially in I/R heart disease, the purpose of this article is to review the cardiodepressant role of these cytokines and their release in I/R injury.

Erythropoietin (Epo) has a long-lasting history as the hormon that allows production of red blood cells. It is now well established that, besides erythropoiesis, Epo has the ability to sustain proliferation of myeloid lineages. More recently, extra-haematological roles have been described for Epo. Its receptor, EpoR, has been detected at the membrane of several neoplastic and normal cell types from the central nervous system and other non haematological cell lines. Whereas Epo-EpoR have been detected several years ago in some extra-haematological normal lineages, their role has long been underestimated whereas they may be crucial for proliferation and survival. Consequently, efforts have recently increased to identify the precise role of Epo-EpoR in a variety of cell types. This allowed identification of physiologically relevant targets that led to original therapeutic strategies.

Background:Severity of illness is not an important determinant of drug-compliance. In this paper we hypothesize that the perceived severity of illness rather than the true severity of illness is a determinant of drug-compliance. If this is true, then it will be worthwhile for physicians to look for factors determining this perceived severity of illness. Objectives: (I) To test in a prospective survey whether this hypothesis can be confirmed in mildly hypertensive patients, and (II) to identify factors determining their perceived severity of illness. Methods: 450 patients were invited to participate in a prospective survey if their systolic blood pressure had been between 140 and 170 mm Hg and their diastolic blood pressure between 90 and 100 mm Hg despite treatment, for at least three clinic visits. Based on previously published data three factors possibly contributing to the perceived severity of hypertension were identified: (1) objective medical information, (2) expected physical symptoms, and (3) a positive social identification with fellow-patients. These factors were used as independent determinants in a multiple linear regression model with perceived severity of hypertension as outcome variable. Subsequently, this outcome variable together with patient characteristics was used as an independent variable in a multiple logistic regression model with drug-compliance as outcome variable. Results: 176 patients, mean age 62 years, 52% females, completed the study. In the multiple linear regression analysis all of the three identified factors were statistically significant predictors of the perceived severity of hypertension with betavalues from 0.22 to 0.26, and p-values between 0.031 and 0.004. The multiple logistic regression analysis demonstrated that, after adjustment for gender, age, school, and general health status, the perceived severity of hypertension was a significant determinant of drug-compliance at p = 0.040. Discussion: The present study shows what information patients use to conclude on the level of their blood pressure being too high or not. This information can be used to better understand the patients' ideas about health and possibly to influence these ideas. Patients' conclusion about the level of their blood pressure predicted their drug-compliance. Our study increased insight into the psychology of the patient and the results may be helpful to physicians in order to further understand and influence patient behaviors, particularly, adherence to antihypertensive medication.

Defects in the regulation of neo blood vessel growth (angiogenesis) or in vessel repair are major complications in many diseases, such as cancer, diabetes, atherosclerosis and myocardial infarction. In these diseases it was shown that the number of circulating endothelial progenitor cells (EPC) was altered. This has been associated with the angiogenic status and patient prognosis. However, the regulation of angiogenesis depends not only on the number of circulating EPC but also on their functions. EPC are bone marrow derived cells that are recruited into the peripheral blood in situations of vascular repair/angiogenesis or vascular stress. EPC are believed to exert their function using mainly two strategies: activating locally the endothelial cells and/or differentiating into mature endothelial cells that integrate the damaged vessels. To do this, EPC must home to “angiogenic active” sites, adhere to the activated/damaged endothelial cells or to the extracellular matrix and participate in the endothelial activation/repair process. In vitro and in vivo experiments using animal models revealed the importance of various signalling pathways in these processes and, in patients, new therapeutic strategies are being developed based on the specific functions of EPC. Although the role of EPC in vessel repair in disease is not totally understood, it becomes clear that the activation state of these cells is critical for the vessel repair process. Our previous work generated a detailed gene expression profile of EPC during the endothelial differentiation process in vitro. With this information, it has been possible to identify numerous molecular targets crucial for EPC differentiation and function and to test their involvement in EPC function during wound healing or tumor angiogenesis. The importance of EPC identification, activation state and function in vascular repair and in angiogenesis in disease will be discussed in this review.

Soluble CD40 ligand (sCD40L) is involved in the pathogenesis of risk factor-related vascular damage and has been regarded as a molecular link between inflammation, thrombosis and angiogenesis. Given the increasingly recognized theory that hypertension is in part an inflammatory disorder, the contribution of CD40/CD40L dyad is becoming one of the outstanding puzzles in the pathophysiology of hypertension. CD40/CD40L signaling appears, in fact, like a versatile pathway that vehicles information within vascular cells. Several distinct lines of investigation in the context of hypertension dealing with low-grade inflammation are now merging, with CD40/CD40L system as the missing link. As an example, recent data suggest that the vasoactive peptide angiotensin II promotes and augments the inflammatory activation induced by CD40/CD40L ligation in human vascular cells. Accordingly, sCD40L levels are elevated in hypertensive patients and might discriminate hypertensive patients at a high risk of cardiovascular events. This review will summarize the present understanding of the contribution of sCD40L to inflammation, thrombosis and neoangiogenesis in hypertension. Furthermore, given the well established effects that antihypertensive drugs exert on the vasculature beyond blood pressure lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on these phenomena.

Mechanisms through which major risk factors accelerate diabetic angiopathy include low density lipoprotein (LDL) oxidation and advanced glycation end products (AGEs) formation. Lectin-like oxidized LDL receptor (LOX-1) is a newly identified vascular receptor for oxidized LDL (oxLDL) and AGEs. LOX-1 is up-regulated in vascular endothelium of diabetic animals and thus may be relevant to the development and progression of human diabetic vasculopathy. The mechanisms responsible for LOX-1 induction in diabetes remain unclear but appear to involve metabolic and inflammatory stimuli relevant to diabetes. Such factors may impact on LOX-1-mediated pro-atherogenic events, including endothelial dysfunction and plaque destabilization. Previous studies have shown that drugs commonly used in the treatment of type 2 diabetic patients, including statins and antidiabetic agents, inhibit endothelial LOX-1 expression. This review summarizes recent advances related to the role of LOX-1 in macrovascular diseases, its regulation by some derangements commonly found in diabetic patients and its modulation by vasculoprotective drugs.

Vascular disease (VD) and its complications are the leading cause of morbility and death in modern civilisations. Primary VD is a very complex and multifactorial process which is still not well understood. Recent studies provide clear and convincing evidences that genetic risk factors (gene polymorphisms) contribute significantly to the pathogenesis and expression of VD. Thus, we have to analyse the interaction of multiple polymorphisms in multiple genes coding for several proteins involved in the molecular etiopathogenesis of VD. All these polymorphisms are interacting among them, enhancing or antagonizing their pathogenic effects, and at the same time, their final phenotypic expression is constantly modulated by other non-genetic factors (environmental and behavioural). Thus, gene-environment interaction analysis would be crucial for the correct etiopathogenic evaluation. According to a particular assortment of positive and negative gene variants (alleles) present in their genetic pool some individuals develop VD without manifesting very extreme levels of any of the classical risk factors while other individuals remain free of disease despite exposure to several risk factors. Taking into account that this heterogeneity is due to their different genetic susceptibility it is necessary to make an analyse in deep including all genetic polymorphisms which have been involved in the vascular etiopathogenesis in order to design the most appropriate intervention strategy. Using a more accurate genetic polymorphism analysis it would be possible to predict complications in order to make prevention designing an individualized drug therapy on the basis of a person's genetic makeup. However, an accurate genetic testing is not being used as often as it is expected because there are so many polymorphisms to consider and DNA tests available to analyse them are usually dispersed throughout different laboratories because they are not included in an unified protocol. In this sense, DNA-Chip technology used as susceptibility (predisposition) testing has evolved into a powerful tool providing informative data from multiple loci in complex diseases like VD (where multiple genetic alterations contribute, but each on a small scale). This technology could greatly reduce health care costs by reducing the number of useless diagnostic tests making possible the genetic dissection of complex human diseases. The proposed paper will discuss these topics with special emphasis on how genetic polymorphisms influence in the individual susceptibility to develop vascular disease and its complications as well as the way that may affect individual responses to several drugs used in the VD management.

The ever-increasing prevalence of cardiovascular disease (CVD) associated with obesity is linked through signaling pathways within adipose tissue. Adipose tissue functions as an endocrine organ, producing and secreting a variety of bioactive molecules. In obesity, the adipose tissue itself undergoes changes in cell size which alters its normal physiological function. Altered adipocyte function changes production and secretion of adipokines, such as leptin, adiponectin, angiotensinogen, plasminogen activator inhibitor-1, resistin, and several inflammatory molecules. Adipokines interact with other tissues and cells in the body, including many pathways linked to CVD. Future research in the area of obesityrelated CVD requires further investigation into a combination of lifestyle and pharmacological therapies that alter adipokine production by reducing adipocyte size.