Current Drug Targets - Volume 4, Issue 6, 2003

The present Hot Topic issue of Current Drug Targets focuses on inflammatory markers and mediators and discusses these in the context of pathophysiology, mechanisms, and management of the cardiovascular dysmetabolic syndrome. Cardiovascular disease is the leading cause of death in people with diabetes. The risk of first myocardial infarction (MI) in diabetes patients is similar to that of recurrent MI in nondiabetic persons who have had a previous MI. Thus, diabetes is not merely a risk factor for cardiovascular disease but a coronary artery disease (CAD) risk-equivalent [1-3]. Although the degree of glycemia (as assessed HbA1c) is an independent predictor of coronary risk [4], hyperglycemia is one of several major etiological factors for macrovascular complications. Thus, whereas a policy of intensive glucose control significantly prevents microvascular complications [5-7], a broader policy involving multiple risk factor reduction must be pursued in order to prevent the macrovascular complications of diabetes [8]. The development of effective interventions for reducing the burden of macrovascular disease can be greatly facilitated by a fuller understanding of the mechanisms that underlie this burden. The insulin resistance syndrome predisposes to macrovascular complications of type 2 diabetes. This condition, also known as the metabolic syndrome, Syndrome X, cardiovascular dysmetabolic syndrome, etc.[3,9], often precedes the diagnosis of type 2 diabetes by several years. Features of the metabolic syndrome include upper body obesity, hyperinsulinemia, hypertriglyceridemia, increased serum LDL-cholesterol and decreased HDL-cholesterol levels, hypertension, hyperuricemia, and a pro-coagulant state, among others. Endothelial dysfunction also tracks the severity of insulin resistance [3,9,10]. The metabolic syndrome affects millions of pre-diabetic persons in the United States, is associated with a two-fold increased risk for CAD, and has recently been allocated the International Classification of Diseases (ICD)-9 code of 277.7. Major criteria for diagnosis include abdominal obesity, hypertriglyceridemia (> 150 mg / dl), hypertension (>130 / 80 mmHg), low HDL-cholesterol (> 40 mg / dl in men; >50 mg / dl in women) and impaired fasting glucose (> 110 mg / dl). The exact mechanisms linking the metabolic syndrome to atherosclerosis are complex and incompletely understood. Recent studies increasing implicate inflammatory and bioactive products of adipocytes in the pathophysiology of insulin resistance and macrovascular disease. The association between insulin resistance and dyslipidemia appears to be triggered by increased free fatty acid (FFA) release from adipose tissue. Central obesity and the resultant increase in portal FFA flux lead to enhanced lipoprotein synthesis, insulin resistance, endothelial dysfunction and increased plasma levels of plasminogen activator inhibitor (PAI)-1. These alterations create a milieu favorable for the development of atherosclerosis and thromboembolic disease [11,12]. Coronary artery disease, the leading macrovascular complication, accounts for most of the diabetes-related mortality. Compared with nondiabetic persons, CAD occurs at a younger age, and is particularly prevalent among diabetic women. Sadly, myocardial infarction carries a worse prognosis, and angioplasty gives less satisfactory results, in diabetic patients compared with nondiabetic individuals. Pro-inflammatory signals and specific cytokines and other products of adipose tissue are emerging as potent mediators of metabolic and vascular processes. The growing evidence suggests that the inflammatory state may constitute a platform for convergence of insulin resistance, atheroclerosis, and macrovascular disorders [11]. Such adverse interactions between pro-inflammatory states and macrovascular disease probably also explain the poor prognosis following coronary events or interventions in the setting of diabetes. Clearly, diabetes mellitus leads to accelerated atherosclerosis through a variety of mutually reinforcing mechanisms, many of which remain to be fully elucidated [1]. A fuller understanding of the mechanisms that underlie the multi-fold increase in the prevalence of cardiovascular, cerebrovascular, and peripheral vascular diseases in patients with diabetes is of utmost priority. In this issue of Hot Topics, Dr. Pierre Theuma and Dr. Vivian Fonseca from Tulane University discuss Novel Cardiovascular Risk Factors and Macrovascular and Microvascular Complications of Diabetes, highlighting the possible roles of endothelial dysfunction, subclinical inflammation, impaired fibrinolysis, microbial infection, and hyperhomocysteinemia, among others. The discussion by Drs. Theuma and Fonseca is followed by a discussion of Insulin resistance as a Proinflammatory State: Mechanisms, Mediators, and Therapeutic Interventions by researchers from the Dandona Laboratory at State University of New York at Buffalo. In their article, Drs. Garg, Tripathy, and Dandona review current understanding of insulin resistance as an inflammatory disease and discuss their recent work on the effect of therapeutic interventions. In the next article titled “Activated T Lymphocytes in Type 2 diabetes: implications from in vitro studies”, Dr. Frankie Stentz and Dr. Abbas Kitabchi from the University of Tennessee, Memphis discuss novel and intriguing ideas that extend immunopathologic frontiers from the classical area of type 1 diabetes to insulin resistance and type diabetes phenotypes. The authors reason that activation of T-lymphocytes shares some similarities with oxidative stress, both conditions being associated with a proinflammatory state. This notion also extends to the growing understanding that metabolic and vascular disease states, such as insulin resistance, type 2 diabetes, and atherosclerosis, may themselves share proinflammatory etiologies. Finally, a state-of-the-art review on the emerging role of aldosterone as a proinflammatory / fibrogenic mediator in cardiac disease is by Drs. Karl Weber, Ivan Gerling, Mohammad Kiani and their multidisciplinary research team from the University of Tennessee, Memphis. The neurohumeral activation that accompanies congestive heart failure is discussed in the context of concomitant induction of oxidative / nitrosative stress, adverse vascular remodeling, and immunomodulation. Unravelling the ramifications of the athero-inflammatory cascade in human metabolic and cardiovascular disorders is an ongoing effort in numerous laboratories and clinical research centers. It is hoped that these vigorous efforts will uncover novel and compelling targets for the development of rational and effective interventions for the prevention and treatment of macrovascular complications of diabetes and prediabetes. References [1] Beckman, J.A., Creager, M.A., Peter Libby, P. (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287, 2570-2581. [2] Haffner, S.M., Lehto, S., Ronnemaa, T., et al. (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N. Engl. J. Med. 339, 229-234. [3] De Fronzo, R.A., Ferrannini, F. (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14, 173-194. [4] Singer, D.E., Nathan, D.M., Anderson, K.M., Wilson, P.W.F., Evans, J.C. (1992) Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes 41, 202-208. [5] The Diabetes Control and Complications Trial Research Group. (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N. Engl. J. Med. 329, 978-986. [6] Ohkubo, Y., Kishikawa, H., Araki, E., et al. (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract. 28, 103-117. [7] Stratton, I.M., Adler, A.I., Neil, H.A., Matthews, D.R., Manley, S.E., Cull, C.A., Hadden, D., Turner, R.C., Holman, R.R. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321, 405-412. [8] Moneva, M., Dagogo-Jack, S. (2002) Multiple drug targets in the management of type 2 diabetes. Curr. Drug. Targets. 3, 203-221. [9] Stuhlinger, M.C., Abbasi, F., Chu, J.W., Lamendola, C., McLaughlin, T.L., Cooke, J.P., Reaven, G.M., Tsao, P.S. (2002) Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287, 1420-1426. [10] Taniguchi, A., Nakai, Y., Fukushima, M., et al. (2002) Ultrasonographically assessed carotid atherosclerosis in Japanese type 2 diabetic patients: Role of nonesterified fatty acids. Metabolism 5, 539-543. [11] Moller, D.E. (2002) Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol. Metab. 11, 212-217. [12] Dagogo-Jack, S. (2002) Management of diabetes and prevention of heart disease. Cardiology Special Edition 8, 11-14.

Nucleoside analogues are widely used for the treament of hematological malignancies and solid tumors. Their activity is based on the interference with cellular targets involved in the metabolism of physiological nucleosides and DNA synthesis. Unfortunately, various resistance mechanisms decrease the activity of these drugs, reducing their clinical efficacy. Here, we review different resistance mechanisms responsible for decreased in vitro and in vivo nucleoside analogue activity, and some of the strategies proposed to circumvent constitutive or acquired drug resistance.

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.

P-glycoprotein, the human MDR1 gene product and cancer multidrug resistance-associated ATP-binding cassette transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-glycoprotein in the secretion of several T cell- and antigen presenting cellderived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that Pglycoprotein serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional immune responses is now established. Here, we will review the current understanding of Pglycoprotein function in T cell activation and antigen presenting cell function, which are relevant to the fields of clinical transplantation and autoimmunity, and summarize the evidence for in vitro and in vivo immunomodulatory actions of several known P-glycoprotein-inhibiting agents currently in clinical use for other indications. We suggest that it is the Pglycoprotein- inhibitory function of many of these agents that underly their immunoregulatory capacities. Thus, the established immunoregulatory function of P-glycoprotein and the availability of P-glycoprotein-inhibitory drugs raise the possibility that P-glycoprotein may represent a promising novel therapeutic target for immune modulation in acute and chronic allograft rejection, and cell-mediated autoimmune disorders.

Morbidity and mortality from diabetes mellitus remain high despite managing the traditional risk factors. Recent data imply that the pathophysiology of macrovascular and microvascular complications involve other factors. The metabolic syndrome precedes the onset of type 2 diabetes by many years. Early treatment of individuals with this syndrome might delay the onset of diabetes and its complications. Endothelial dysfunction, subclinical inflammation and impaired fibrinolysis may contribute to progression of macrovascular as well as microvascular complications. The roles of infection and hyperhomocysteinemia are less clear but may be significant. This review discusses the current knowledge on these “non-traditional” risk factors and therapies to improve them.

Insulin resistance has been recognized as an inflammatory disease based on the scientific evidence collected over the last decade. Inflammatory markers like CRP, PAI-1, IL-6 are present in higher concentrations in insulin resistant people than in normal people. Mechanisms, linking inflammation to insulin resistance are being explored and progress has been made in this direction. TNFα has been shown to be responsible for insulin resistance in obese subjects. Macronutrient intake may also induce inflammation whereas fasting has antiinflammatory effects. Insulin itself has been found to be anti-inflammatory and this action may be useful in many disease states. Thiazolidinediones, such as rosiglitazone that act primarily as insulin sensitisers, have a profound anti-inflammatory and potentially antiatherosclerotic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis, the major complication of insulin resistance.

The number of subjects with Type 2 diabetes (DM2) has risen significantly in the last ten years. Obtaining sufficient human tissue to study this disease process as well as many other diseases is generally difficult. T lymphocytes offer a unique opportunity for these studies. Although resting human peripheral T-lymphocytes are devoid of insulin receptors, these receptors emerge upon activation of cells by specific antigens or mitogens. Concomitant with the insulin receptors, two other growth factor receptors (IGF-1 and IL-2) also emerge on the T lymphocyte cell surface along with intracellular signal transduction mechanisms and insulin degrading enzyme (IDE). After binding to its receptor, insulin has been shown to exert its classical effects on carbohydrate metabolism in the stimulated T- cell; thereby, validating the use of activated T-lymphocytes for studying the pathogenesis of metabolic and immune disorders and the mechanism(s) by which insulin exerts its effects. In activated T-lymphocytes, insulin stimulates glucose uptake, glucose oxidation, pyruvate flux and pyruvate dehydrogenase activity, amino acid transport, lipid metabolism and protein synthesis. Through its ability to enhance nutrient uptake and raise the levels of intermediary cellular metabolism, insulin is believed to maintain the allo-activated state of lymphocytes, enhance T-Lymphocyte responsiveness, and support or possibly promote the actions of immuno-derived regulatory growth and differential factors. Since insulin enhances energy requirements and protein synthesis necessary for appropriate T-cell functions, defects in insulin action may lead to inappropriate immunoresponses in various metabolic states such as in diabetes. Studies from our lab have found insulin binding, processing, and responsiveness in phytohemagglutinin(PHA)-activated T-cells are reflective of the donor's glycemic status and ambient insulin levels in subjects with Type 1 and Type 2 diabetes (DM2) and other insulin resistant states. Our studies show that patients with diabetic ketoacidosis and hyperglycemia have increased proinflammatory cytokines and activated CD4+ and CD8+ T lymphocytes. The diabetic state, where effective insulin concentrations are low and both glucose and free fatty acids are high, provides an environment of oxidative stress and activation of the inflammatory pathways. The mechanisms underlying insulin action, in general, or in the CD4+ and CD8+ T-lymphocytes, in particular, have not been clearly elucidated. Due to the accessibility of obtaining these cells from patients, activated T-lymphocytes offer the potential of studying diabetes and other disease in human subjects.

Heart failure is a major health problem of epidemic proportions. Irrespective of its etiologic origins, a dysfunction of this normally efficient muscular pump is associated with systemic consequences, a progressive downhill clinical course and poor prognosis. Ventricular dysfunction is ultimately accompanied by neurohormonal system activation that accounts for: the congestive heart failure syndrome; an induction of oxi / nitrosative stress; adverse vascular remodeling; and activation of the immune system that contributes to a wasting syndrome known as cardiac cachexia. Circulating effector hormones of the renin-angiotensin-aldosterone system are an integral feature of this neurohormonal activation; they have systemic consequences. Insights into the pathophysiology of heart failure will identify improved methods of prevention, including biomarkers to aid in its detection and identification of risk, and to the development of specific drug targets. Herein we address one aspect of the neurohormonal profile of heart failure, namely that related to aldosteronism. Our focus is directed at the link between aldosteronism and its adverse influence on coronary vasculature structure, a proinflammatory / fibrogenic cardiac phenotype, which is based on an immunostimulatory state that includes activated peripheral blood mononuclear cells.