Cardiovascular & Haematological Disorders - Drug Targets - Volume 9, Issue 3, 2009

Autoimmune haemolytic anaemia (AIHA) is characterised by the production of autoantibodies that target determinants on red blood cells. Current treatments rely on generalised immunosupression or cytotoxic treatments that may have potentially harmful side effects. Whilst the underlying cause of disease remains unknown, recent advances in our understanding of CD4+ helper T cell (Th) subsets that drive and control the autoimmune response have important implications for the development of novel immunotherapy. The effector arm of the adaptive immune response is now known to include at least three Th subsets: Th1, Th2 and the recently described Th17. In human AIHA, the targets of the autoimmune response in most patients, the Rhesus (Rh) proteins, have been identified and sequenced, providing the opportunity to study antigen specific responses. The effector Th response is dominated by Th1 cells that are under the control of IL-10 dependent regulatory cells (Tr1). These Th1 responses can be suppressed, with synthetic peptides that are recognised by the Tr1 cells. Such specificity would provide an extremely potent tool in the treatment of autoimmune disease. This review discusses the recent advances in our understanding of helper T cell subsets and the implications for the development of specific immunotherapy in autoimmune disease, using the well characterised responses in AIHA as an example.

The function of the platelet collagen receptor, 65-kDa, specific for type I collagen (CI), in eukaryotic cells remains elusive. In order to examine the effect of posttranslational modification of the receptor, we have made a construct, which contains the 65-kDa cDNA ligated into pcDNA3 (eukaryotic expression vector) by using standard cloning methodologies. The construct was transfected into CHO (CHO-65) cells, which expressed the protein, detectable by immunoblots [using the anti-65kDa antibodies (65-Ab)], and flow cytometry confirmed expression on the cell surface. A binding assay was used to evaluate the interaction of the expressed protein with CI. A chemically synthesized hybrid peptide (cHyB) containing the active peptides derived from the platelet receptors for types I and III collagen (9 amino acids each with a linker of 10 amino acid residues) inhibited the binding of the 65-Ab and FITC-CI on the CHO-65 cells. These results suggest that the 65-kDa proteins play a role in the interaction with CI and could potentially lead to new therapeutic development for an anti-platelet agent.

Vascular smooth muscle cells (VSMCs) respond to arterial wall injury by intimal proliferation and play a key role in atherogenesis by proliferating and migrating excessively in response to repeated injury, such as hypertension and atherosclerosis. In contrast, fully differentiated, quiescent VSMCs allow arterial vasodilatation and vasoconstriction. Exaggerated and uncontrolled VSMCs proliferation appears therefore to be a common feature of both atherosclerosis and hypertension. Phosphorylation/dephosphorylation reactions of enzymes belonging to the family of mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) play an important role in the transduction of mitogenic signal. We have previously shown that among extracellular signal-regulated protein kinases (ERKs), the 42 and 44 kDa isoforms (ERK1/2) as well as Akt and cytosolic phospholipase 2 (cPLA2) participate in the cellular mitogenic machinery triggered by several VSMCs activators, including insulin (INS). The ability of INS to significantly increase VSMCs proliferation has been demonstrated in several systems, but understanding of the intracellular signal transduction pathways involved is incomplete. Signal transduction pathways involved in regulation of the VSMCs proliferation by INS remains poorly understood. Thus, this review examines recent findings in signaling mechanisms employed by INS in modulating the regulation of proliferation of VSMCs with particular emphasis on PI3K/Akt, cPLA2 and ERK1/2 signaling pathways that have been identified as important mediators of VSMCs hypertrophy and vascular diseases. These findings are critical for understanding the role of INS in vascular biology and hyperinsulinemia.

Epidemiological data have demonstrated a strong relationship between blood pressure (BP) and cardiovascular disease (CVD) risk and have shown the importance of systolic BP (SBP) as a determinant of such risk. The importance of BP as a risk factor has been further emphasized by a World Health Organization (WHO) report which identified high BP as one of the most important preventable causes of premature morbidity and mortality in developed and developing countries. There is now data available on the safety and effectiveness of different classes of BP-lowering drugs, including diuretics, angiotensin-converting enzyme inhibitors (ACE-Is), dihydropyridine and non-dihydropyridine calcium channel blockers (CCBs), beta-blockers and angiotensin receptor blockers (ARBs). In this review we discuss classification of BP stages, goal of therapy, lifestyle modifications and optimal BP control in individual patients. The detection and optimal treatment of hypertension is likely to significantly ameliorate CVD risk.

Acute heart failure (AHF) represents a major public health problem due to its high prevalence, high rates of mortality and readmissions and significant healthcare costs. Patients with AHF and low cardiac output represent a small subgroup of patients with very high mortality rates that require inotropic support to improve cardiac systolic function. Classical inotropic agents, such as β1-adrenergic agonists (dobutamine, dopamine) and phosphodiesterase III inhibitors (milrinone, enoximone) improve symptoms and hemodynamics by increasing free intracellular Ca2+ levels, but also increase myocardial O2 demands and exert arrhythmogenic effects. These actions explain why these drugs increase both short- and long-term mortality, particularly in patients with AHF and coronary artery disease. Thus, we need new inotropic agents that do not increase cytosolic Ca2+ or myocardial oxygen demands or produce arrhythmogenesis for the treatment of high-risk patients with (AHF) and low cardiac output. This review describes three new classes of investigational agents: levosimendan, a calcium sensitizer and potassium channel opener, istaroxime, the first new luso-inotropic agent and cardiac myosin activators.

Targeted drug delivery system, consisting of a guidance component, a transport vehicle and the drug, is aiming at distributing the drugs to a specific organ or cell type in a sufficient concentration to achieve the high efficiency and alleviate the side-effects of the drugs. During the past decade, besides physical and chemical methods, biological strategies have been developing at an amazing speed improving the drug targeting system. These include: i) searching for guidance components, which include integrin ligands, extracellular matrix proteins, carbohydrates, vitamins, antibodies, nucleic acid aptamers and peptides, leading the whole system to the targeting sites; ii) development of the transport vehicles, such as polymers and plasmid/virus vectors that play the role in carrying drugs and protecting them on their way to the destination; and iii) the design or selection of an effective drug, the “final bullet” that functions on the targeting site, to test the efficiency of the system. Here, we briefly review the recent advances on the development of the most essential targeted drug delivery systems and strategies, and particularly focusing on the progress in discovery of the ligand components and construction of carrying vehicles for drug targeted delivery systems. In addition, we briefly discuss the prospect of this field.

Leukocyte-endothelial interaction plays an important role in the early phase of the development of diabetic retinopathy. It has been studied extensively linking inflammatory processes to its development conducted to date in rats and mice, and have focused on insulin-deficient models. The molecular and functional changes that are characteristics of inflammation have been detected in retinas from diabetic animals and humans with involvement of multiple pathways that results in the final sequelae of increased permeability of the blood retinal barrier and finally ischemia that drives angiogenesis. Increased expression of Intracellular adhesion molecules heralds the onset of changes that results in attraction of leucocytes such as neutrophils. The consequent release of cytokines and growth factors such as vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha, and interleukin 1-Beta results in increased permeability and retinal edema. Other indirect mediators involved include pathways such as the protein kinase C (PKC), renin-angiotensin system, enzymes such as the poly ADP-ribose polymerase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, nitric oxide synthetase and finally advanced glycation products. Therapy for early diabetic retinopathy may inhibit one or more of these pathways using drugs that can be given systemically, with local ocular applications having a more direct effect as in other eye diseases.