Cardiovascular & Haematological Disorders - Drug Targets - Volume 8, Issue 4, 2008

In HIV infected patients an increased occurence of cardiac events has been demontrated from the introduction of highly active antiretroviral therapy (HAART). Antiretroviral drugs' regimens are, in fact, associated with several metabolic side effects, such as dyslipidemia, impaired glucose metabolism and abnormal body fat distribution, that increase the cardiovascular risk of HIV subjects. In addition, HIV infection itself, the chronic inflammatory status and the relevant presence in this population of some of the traditional cardiovascular risk factors contribute to an higher incidence of cardio and cerebrovascular events. In last years several studies showed the occurence of carotid vascular impairment in patients in treatment with protease inhibitors (PI). Similarly the DAD Study reported an increase of 26% of the risk of myocardial infarction in patients on HAART and that this risk is indipendently associated with longer exposure to PI, even after multivariate adjustments. A correct evaluation of the metabolic status before starting HAART and an adeguate control of the drugs-related metabolic abnormalities may reduce the incidence of cardiac events and still improve HIV patients prognosis. This review will focus on the metbolic effects of antiretroviral drugs and to the contribution of combination antiretroviral therapy on cardiovascular risk.

In addition to their canonical genomic action, sex hormones exhibit acute actions, which are designated as the non-genomic action. Non-genomic action takes only several seconds to minutes and takes place in a membrane-delimited signal pathway. We recently find in cardiac myocytes that testosterone, progesterone, and a high-concentration of 17β- estradiol acutely shorten cardiac repolarization time by regulating L-type Ca2+ current (ICa,L) and slowly-activating delayed rectifier K+ current (IKs). The regulation of ICa,L and IKs occurs via the non-genomic pathway involving sequential activation of c-Src, PI3-kinase, Akt, and eNOS and resultant release of nitric oxide (NO), which occur in the caveolae/ lipid raft domain. NO inhibits ICa,L, only when ICa,L had been activated by sympathetic nervous system stimulation via antagonistic action between cAMP/protein kinase A and cGMP/protein kinase G/phosphodiesterase signals. NO likely to enhance IKs in the basal condition via the protein s-nitrosylation mechanism. The non-genomic regulation by sex hormones is a novel regulatory mechanism of cardiac ion channels, and may be involved, in part, in the development of gender difference and dynamic fluctuation of QTc interval and arrhythmic risk during the menstrual cycle.

Cell adhesion molecules are ubiquitously expressed proteins playing a central role in controlling cell migration, proliferation, survival, and apoptosis. Besides their key function in physiological maintenance of tissue integrity, adhesion molecules play an eminent role in various pathological processes. In cardiovascular disorders, cell adhesion molecules are particularly involved in atherogenesis and atherosclerotic plaque progression. They also play a critical role in myocardial infarction and reperfusion damage and a minor role in valvular stenosis and cardiomyopathy. Their common denominator: An increased expression of adhesion molecules involved in leukocyte extravasation and accumulation. Leukocyte extravasation is a multistep process, mediated by several cell adhesion molecules including selectins (P-, E- and L-), integrins and members of the Ig superfamily (ICAM-1, VCAM-1). These molecules can be targeted for imaging purposes (e.g. to identify atherosclerotic plaques) or can serve as biomarkers for plaque destabilization. Furthermore, cell adhesion molecules can serve as drugable targets to prevent leukocyte extravasation where warranted to decrease inflammatory tissue damage (e.g. reperfusion injury). Current techniques involve blocking of binding sites, targeted drug delivery using liposomes and polymeric particles as carriers or imaging of inflammation sites using labeled cells or antibodies. This review focuses on the role of cell adhesion molecules in cardiovascular disease and the use of targeting adhesion molecules for imaging purposes and local drug delivery in cardiovascular medicine.

Chronic myelogenous leukemia (CML) is a hematological malignancy that is characteristic by as expansion of myeloid cells and their premature release into the circulation. The molecular cause of CML is the fusion oncoprotein Bcr- Abl whose constitutive tyrosine-kinase (TK) activity maintains enhanced signaling through multiple signal transduction pathways and confers proliferative and survival advantage to CML cells. These effects can be largely suppressed by TK inhibitor Imatinib mesylate, currently the leading drug in CML treatment. However, Bcr-Abl contains also additional functional domains, in particular a DBL homology (DH) domain with guanine-exchange function (GEF) which can activate small GTPases of Rho family and a Src-homology3 (SH3) domain which recruits other proteins with GEF activity. Bcr-Abl affects among others the RhoA/ROCK/LIM/cofilin pathway that regulates the actin cytoskeleton assembly and thereby the cellular adhesion and migration. This review deals in detail with the known points of interference between Bcr-Abl and Rho kinase pathways and with the effects of Imatinib mesylate on Rho signaling and cell adhesion to the extracellular matrix (ECM) components. The potential protein targets related to Bcr-Abl non-kinase activity are discussed.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Aspirin target cyclooxygenase (cox) enzymes and inhibit the synthesis of prostanoids. These drugs were originally developed to reduce the cardinal signs of inflammation, primarily pain. Prior to understanding their mechanism of action, investigations of Aspirin response in humans have revealed a protective effect on the cardiovascular system. Daily low-dose Aspirin is a well-established and prevailing treatment for the prevention of arterial thrombosis. Platelet inhibition by Aspirin results from the irreversible inhibition of cyclooxygenase- 1 enzyme and prevention of thromboxane A2, a potent aggregatory agent, formation. In an effort to develop drugs with a safer profile for the stomach, a new form of cyclooxygenase was discovered. Subsequently and with the development of cloning strategies, cyclooxygenase-2 was cloned and characterized to have a profile of induction associated with the inflammatory reaction. This provided the rationale to target cox-2 enzyme and development of cox-2 selective drugs such as Vioxx and Celebrex. Coxibs were initially a successful treatment for arthritic patients also providing a reduction in gastric ulceration compared to traditional NSAIDs. Further investigations on the drug response to coxibs revealed a detrimental effect; the increase of myocardial infarctions, and the withdrawal of Vioxx from the market. The current theory to explain the harmful effect of coxib suggests the disruption of the platelet-endothelium interaction and selective inhibition of endothelium cox-2 activity depriving the cardiovascular system of vascular prostacyclin with anti-aggregatory activity. The balancing prostanoid theory to explain coxib cardiovascular complications was recently opposed. Recent investigations of Aspirin drug response have unraveled genetic variations in the cox-1 gene that are associated with the occurrence of Aspirin sensitivity or lack of protections against cardiovascular accidents. Screening for cox-1 gene variants will identify susceptible patients and reduce undesirable side-effects associated with Aspirin. Here we review recent findings in the cyclooxygenase-1 pathway and potential impact for the development of therapeutics that would segregate antithrombotic benefit from bleeding risk. Over 100 years following the initial use of Aspirin, cyclooxygenase inhibitors continue to be instrumental in our understanding of cardiovascular homeostasis and how the cyclooxygenase pathways are disrupted in disease.

Phagocytes were first described 120 years ago. Although the molecular mechanisms involved in initiating phagocytosis (through Fc or other receptors) are still not fully understood, the roles of phagocytes in innate and adaptive immunity have been well studied. Phagocytes in the reticuloendothelial system, particularly macrophages, have been implicated in the clearance of senescent blood cells. The destruction of these cells may be primarily mediated through an Fcindependent pathway. Fc-independent phagocytosis may also play an important role in platelet clearance, including immune thrombocytopenia (ITP). The two major platelet antigens targeted in ITP are GPIIbIIIa and the GPIb complex. It has been demonstrated that anti-GPIbα antibodies, in contrast to anti-GPIIbIIIa, can induce thrombocytopenia in an Fcindependent manner. We further demonstrated in an animal model that intravenous IgG is not able to ameliorate thrombocytopenia caused by most anti-GPIbα antibodies, though it is effective in anti-GPIIbIIIa mediated thrombocytopenia. Our data was supported by a recent retrospective study of ITP patients. Therefore, identification of antibody specificity (e.g. anti-GPIIbIIIa (Fc-dependent) versus anti-GPIbα (Fc-independent)) in patients may be important for ITP therapy.

Sevelamer hydrochloride is a phosphate binder and its effectiveness to reduce the cardiovascular mortality of dialysis patients has been tested. Sevelamer hydrochloride also contains chlorine, so a decrease in bicarbonate due to chlorine load was anticipated and metabolic acidosis thought to associate with sevelamer hydrochloride has been reported in some papers. We reported that sevelamer hydrochloride exacerbated metabolic acidosis in hemodialysis patients, depending on the dosage. Also a Japanese nationwide survey suggested that sevelamer hydrochloride usage potentially aggravates acidosis in dialysis patients. A multi-institute research study by Edmung et al. has shown that metabolic acidosis, with serum CO2 below 17.5 mmol/L, is by itself associated with increased risk of death in dialysis patients. Furthermore, the Dialysis Outcomes and Practice Patterns Study (DOPPS) revealed that both high (> 27 mmol/L) and low (< or % 17 mmol/L) serum bicarbonate (total CO2) levels were associated with increased risk for mortality and hospitalization. There has not been any significant evidence to show that sevelamer hydrochloride has reduced the cardiovascular mortality of dialysis patients compared with calcium-based binder. Clinicians should check not only the level of chlorine but also the level of total CO2 or bicarbonate during the treatment with sevelamer hydrochloride, and control metabolic acidosis.

The major underlying pathology of most cardiovascular disease is the chronic inflammatory disease of atherosclerosis. Type 2 diabetes, also recognised as an inflammatory condition, accelerates the development of atherosclerosis. Current therapies for atherosclerosis target risk factors such as elevated blood lipids and hypertension and are of strong but limited efficacy. The “response to retention” hypothesis states that atherosclerosis is initiated by the accumulation of lipids through binding to extracellular matrix, and this is specifically the glycosaminoglycan (GAG) chains on proteoglycans. Many vasoactive agonists stimulate changes in the structure of the GAGs which increase lipid binding and the relevant signalling pathways are a potential therapeutic target. It has recently been demonstrated that the actions of transforming growth factor β on vascular smooth muscle proteoglycan synthesis involves signalling through p38 MAP kinase and inhibition of this pathway reduces binding of lipids. Inhibition of p38 MAP kinase will elicit a wide spread antiinflammatory response which may alleviate some of the deleterious processes in cardiovascular tissues. This article explores the potential for the actions of p38 MAP kinase inhibitors directed at proteoglycan synthesis in vascular smooth muscle to contribute to the beneficial outcomes from targeting p38 MAP kinase for the prevention of cardiovascular disease.

The regulation of cellular reduction/oxidation (redox) balance is critically determined by several antioxidant systems such as the thioredoxin-1 (Trx-1) which reduces disulfides on targeted proteins. In addition, intracellular Trx-1 exerts most of its antioxidant properties through scavenging of reactive oxygen species. Moreover, it acts as a cofactor for several enzymes and plays an important role in the regulation of redox-sensitive transcription factors. Several studies have reported that Trx-1 activity can be modulated by the interaction with vitamin D3-upregulated protein (VDUP-1) (also called Txnip for thioredoxin interacting protein-1 or TBP-2 for Trx-binding protein-2). Trx-1 secretion has been reported to occur in conditions associated with oxidative stress and inflammation. Beneficial effects of elevated plasma Trx-1 levels on various pathologies were reported in mice. In conclusion, oxidative stress is an important actor in various pathologies including cardio- and cerebro-vascular diseases. Therefore, controlling the redox status by increasing the activity of Trx-1 seems to be a novel and an attractive approach.

Interest in and use of “natural” remedies has grown exponentially in recent years. Compounds that have attracted considerable attention are the isoflavones, particular those found in soy. This review will provide a critical evaluation of our current understanding of the effects, mechanisms of action, and potential clinical applications of soy isoflavones in hypertension. Current data indicate that soy isoflavones, such as genistein and daidzein and equol, relax vascular smooth muscle both in vitro and in vivo via a combination of mechanisms including potentiation of endothelial-dependent and endothelial-independent vasodilator systems and inhibition of constrictor mechanisms. These effects involve both classical genomic as well non genomic actions. Isoflavone actions are mediated in part via interactions with estrogen receptors where soy isoflavones induce unique receptor conformations and exert tissue dependent effects similar to the selective estrogen receptor modulators. Signaling pathways such as ERK1/2, PI3-Kinase/Akt and cAMP contribute to isoflavone isoflavone activation of eNOS in the vasculature as well. Isoflavones also target the kidney to increase renal blood flow and sodium excretion. Finally, soy isoflavones interact with humoral systems such as the renin angiotensin. Data from animal studies show consistently that the aggregate effect of these actions is attenuation of hypertension. In contrast, studies in humans remain controversial. Recent data also suggest that analogues of isoflavones may possess unique vascular actions. Thus significant opportunity remains for study of the effects and mechanisms of action of soy isoflavones on hypertension in both animals and humans.

Inflammatory cardiomyopathy is a common cause of heart failure developing on a basis of cardiac inflammation. Cardiac inflammation - or myocarditis - is usually triggered by infections or cardiac damage of any cause. Experimental autoimmune myocarditis refers to a CD4+ T cell-mediated mouse model of inflammatory cardiomyopathy. So far, the experimental autoimmune myocarditis model helped us to understand the role of various chemokines, cytokines, and cell subsets in the progression of inflammatory heart disease. Here, we review the current therapeutic options for inflammatory cardiomyopathy, and delineate potential future treatment approaches from the most recent mechanistic insights given by the experimental autoimmune myocarditis model.