Cardiovascular & Haematological Disorders - Drug Targets - Volume 6, Issue 1, 2006

Reactive oxygen species (ROS) contribute to the pathogenesis of cardiovascular diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and diabetes mellitus. Oxidative stress is resulted from excessive generation of ROS that outstrips the antioxidant system. Various agonists, pathological conditions and therapeutic interventions lead to modulated expression and function of oxidant and antioxidant enzymes, including NAD(P)H oxidase, endothelial nitric oxide synthase, xanthine oxidase, myeloperoxidase, superoxide dismutases, catalase and glutathione peroxidase. ROS formed in vascular wall target a wide range of signaling molecules and cellular pathways in both endothelium and vascular smooth muscle, such as transcription factors, protein tyrosine phosphatase, protein tyrosine kinase, mitogen-activated protein kinase, Ca2+-transporting system and protein modification. ROS also have distinct physiological and pathophysiological impacts on vascular cells. ROS contribute to vascular dysfunction and remodeling through oxidative damage by (1) reducing the bioavailability of NO, (2) impairing endothelium-dependent vasodilatation and endothelial cell growth, (3) causing apoptosis or anoikis, (4) stimulating endothelial cell migration, and (5) activating adhesion molecules and inflammatory reaction, leading to endothelial dysfunction, an initial episode progressing toward hypertension and atherosclerosis. Cellular events underlying these processes involve changes in vascular smooth muscle cell growth, apoptosis/anoikis, cell migration, inflammation, and vasoconstriction. The present communication focuses on the biology of ROS signaling in vascular cells, discusses how oxidative stress contributes to vascular damage, and the therapeutic strategies/biotic factors that can prevent or treat ROS-associated cardiovascular disorders.

Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid β (Aβ ), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by β - and γ-secretase, and/or Aβ-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Aβ -like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMGCoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Aβ formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter -secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of A -containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.

Chronic congestive heart failure has become a significant medical burden in the adult and a growing problem in the pediatric age group. While the etiologies of heart failure differ between children and adults, applied medical therapies are generally the same. In this regard, over the last decade, β-adrenergic receptor blockade has become an important component in drug therapy of congestive heart failure in the adult population. A third-generation β-blocker, carvedilol, has now been shown in adult trials to be efficacious in the treatment of heart failure and has been shown to be superior to other similarly used β-blockers. Carvedilol use has been adapted into pediatric heart failure practice although data supporting its efficacy in infants and children are scarce. This review will describe the application of carvedilol in the adult, as it pertains to pediatric practice, review the existing pediatric literature and describe our institution's experience with carvedilol in heart failure therapy.

The aim of this review is (1) to give a rationale for anti-platelet therapy based on mechanisms of platelet rich arterial thrmbosis, (2) to point out the pitfalls involved in monitoring therapy with platelet function tests and (3) to outline the potential clinical applications of such therapy based on the various modes of action of anti-platelet drugs. The primary event in arterial thrombosis is platelet-mediated, either due to increased shear or exposed collagen, followed by fibrin-rich thrombosis. Anti-platelet therapy needs to be monitored but most platelet function tests, now in use, do not reflect in vivo function; the anticoagulant used for blood samples removes extra-cellular calcium ions, platelets are often separated before the test, or very high doses of agonist are used: all of these can give misleading results. We review means whereby platelet function can be monitored in whole blood samples anticoagulated with the pure thrombin inhibitor, hirudin. We review the available methods of modifying platelet activity and are particularly interested in agents that do not cause bleeding. Present therapy causes bleeding by interference with COX1, the P2Y12 receptor or the platelet fibrinogen receptor complex, all of which can be associated with bleeding complications. In contrast, serotonin does not influence formation of haemostatic layers although it is implicated in shear-induced aggregation and thrombus propagation by positive feedback from the large amount of intraplatelet serotonin. We suggest that further investigation of selective serotonin 5HT2 antagonism would allow effective management of intravascular thrombosis without bleeding complications. This would be safer both as prophylaxis and would also allow cardioprotection of vascular patients undergoing surgical operations.

Objective: Hypertensive retinopathy is an important complication and a major site of target organ damage from hypertension. Angiotensin converting enzyme (ACE) has a main role in cardiovascular physiology. It was shown that ACE gene polymorphism is related to plasma concentrations of ACE. We aimed to investigate the relationship between ACE gene polymorphism and hypertensive retinopathy. Methods: One-hundred and eight patients (62 female, mean age; 52.8 ± 7.0 years) with essential hypertension and 30 healthy volunteers were enrolled in this study. Hypertensive retinopathy was diagnosed in a dark room with direct ophthalmoscopy by a single ophthalmologist who was blinded to clinical data. Polymerase chain reaction analysis was used to detect the insertion/deletion (l/D) polymorphism of the ACE gene. Patients were assigned to Group DD, Group ID and Group II. Three genotypic subgroups were compared for hypertensive retinopathy. Results: There were 42 patients (27 female, mean age: 52.4 ± 7.8) in DD group; 51 patients (28 female, mean age: 53.6 ± 6.9) in ID group and 15 patients (7 female, mean age: 51.2 ± 5.6) in II group. Basal characteristics of the patients were similar in the three groups. The genotypic distributions of patients and healthy controls were comparable. Hypertensive retinopathy was determined in 15 (35.7%) patients in DD group, 8 (15.6%) patients in ID group and 2 (13.3%) patients in II group (p<0.05). Conclusion: We found a significant relationship between ACE gene I/D polymorphism and hypertensive retinopathy. Identification of ACE genotype in hypertensive patients might be useful to discriminate the patients who are more susceptible to hypertensive retinopathy.

The giraffe is unique as its head is 2500-3000 millimeters above its heart, thus the giraffe's heart must pump hard enough to overcome the huge hydrostatic pressure generated by the tall column of blood in its neck in order to provide its head with sufficient nutrients and oxygen. Giraffes therefore have exceptionally high blood pressure (hypertension) by human standards. Interestingly, the "unnaturally" high blood pressure in giraffes does not culminate in severe vascular lesions, nor does it lead to heart and kidney failure, whereas in humans, the same blood pressure is exceedingly dangerous and will cause severe vascular damage. Intrinsically, natural selection likely has provided an important protective mechanism, because hypertension develops as soon as the giraffe stands up and erects its neck immediately after birth. Therefore, those individual giraffes who did not tolerate the burden of hypertension presumably developed acute heart failure and renal failure, not surviving to reproductive age. The genes and genotypes of animals that did not survive are thus predicted to have been gradually eliminated from the gene pool by natural selection. By the same process, genes that protect against hypertensive damage would be preserved and inherited from generation to generation. Some unique ingredients of the giraffe's diet may also provide an extrinsic mechanism for the prevention of hypertension and the prevention of fatal end-stage organ damage. The fascinating nature of the protective mechanisms in giraffes may provide a conceptual framework for further experimental investigations into mechanisms as well as prevention and treatment of human hypertension and cardiovascular disease.

Nitric oxide (NO) is a small gaseous molecule with an odd number of electrons and is rather soluble in hydrophobic phases. It was once known for its toxicity in the environment and for its applications in meat curing. After 1980 its importance was discovered in many physiological fields such as vascular regulation, neuronal communication, cytotoxic action by macrophages in bacterial infections etc. On the other side NO is involved in toxic shock, DNA damage and many pathological conditions. In 1992 the journal Science designated it as "molecule of the year" and in the last years there has been an explosion of publications on the subject. The publications are concerned with the spectroscopic characterisation of NO derivatives, with the reactivity of NO with Myoglobin, Cytochrome and Hemoglobin and in particular with the chemical activities and biological applications of nitric oxide donors and nitric oxide scavengers. All such researches have produced until now many patents. The most famous products are Viagra and nitroglycerine (Trinitrin). Particular attention is given to the applications of NO to cardiovascular and hematological disorders. To this aim the authors examine the physiologic activities of NO and the mechanism of its antiplatelet, vasodilatory and antiproliferative action. Studies in animals and humans are also reported. Another section examines the drugs that increase the endogenous production of NO and modulate its activities. The last part is dedicated to the novel antithrombotic agent Nitroaspirin. Methods for NO detection will also be examined.