Cardiovascular & Haematological Disorders - Drug Targets - Volume 7, Issue 4, 2007

Beyond carbohydrate, lipid and protein metabolism, insulin influences hemostasis, vascular tone and angiogenesis. Insulin per se causes a slow-acting vasodilation selectively occurring in skeletal muscle tissue, mainly related to an endothelium-dependent mechanism. Insulin-induced vasodilation is attenuated by the secretion of endothelin-1 and by the stimulation of sympathetic activity. The direct vasodilating effect of insulin is deeply reduced in the insulin-resistant states. The insulin effects on platelet aggregation and inflammatory response are attributable to increased synthesis of nitric oxide, and are deeply reduced in the insulin-resistant states. Furthermore, insulin reduces oxidative stress and promotes angiogenesis and proliferation of vascular smooth muscle cells. The involvement of insulin signalling pathways in these different insulin actions both in insulin sensitive and in insulin resistant states and the concept of “selective insulin resistance” are discussed. The vascular effects of insulin are generally ignored in the clinical practice, despite the evidences that insulin infusion with algorithms aiming to provide an optimal blood glucose control improves the clinical outcomes of patients with severe acute illness and myocardial infarction. Aim of this review is to clarify whether the vascular effects of insulin could represent a new “rationale” for its therapeutical use, independently of the well known metabolic actions.

The ubiquitin-proteasome system (UPS) displays an important quality control function, by removing abnormal proteins from the cytosol, the nucleus and the endoplasmic reticulum. It controls the intracellular levels of short-lived and regulatory proteins important for a variety of basic cellular processes. The pathway involves an enzymatic cascade through which multiple 76-amino acid ubiquitin monomers are covalently attached via a three-step process to the protein substrate, which is then degraded by the 26S proteasome complex. The proteasome is a cylindrical organelle that recognizes ubiquitinated proteins, degrades a large proportion of intracellular proteins, and recycles ubiquitin. Alterations in the proteasome proteolytic pathway have been contributed to protein alterations associated with aging and, in fact, dysregulation of the UPS has been linked to several disease states including neurodegenerative diseases, malignancies, and inflammatory- related diseases. Strong preclinical data now exist supporting the use of reversible proteasome inhibitors to treat a variety of disease states including cancer, autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury. Bortezomib (Velcade®) has recently been licensed for the treatment of patients with multiple myeloma and is also undergoing further evaluation for the treatment of chronic lymphocytic leukemia and a variety of solid tumors. MLN- 519 is a small-molecular-weight lactacystin analogue and is being studied for the potential treatment of inflammatory disease and stroke. MLN-519 has demonstrated a neuroprotective effect in rat models of middle cerebral artery occlusion reducing infarct volume, brain oedema and improves neurological outcome with a therapeutic window of up to 6-hrs. This review article focuses on the recent progress in the use of proteasome inhibitors in nervous system diseases with emphasis on the bench-to-bedside research effort which provided the foundation for clinical development of proteasome inhibitors in the treatment of neurological disorders.

Aspirin protects from cardiovascular events because of its antiaggregant effect. The occurrence of new events in patients who take aspirin has been called clinical aspirin resistance. Many authors believe that aspirin resistance must be detected by biochemical tests, although there is no agreement on which is the best. Nor is there agreement on the term aspirin resistance. Tests used in research laboratories are aggregometry (turbidometric and impedance), tests based on activation- dependent changes in platelet surface, and tests based on activation-dependent release from platelets. Point-ofcare tests are PFA-100, IMPACT and VerifyNow, which can detect platelet dysfunction that may be due to aspirin effect, but their use for this purpose is not yet recommended. Aspirin response may be modified by different factors: patient's compliance, dose, smoking, hyperlipidemia, hyperglucemia, acute coronary syndrome, percutaneous revascularization, recent stroke, extracorporeal circulation, heart failure, exercise, circadian rhythm, absorption, concomitant medications, polymorphisms. Patients with aspirin resistance may have an increased risk of cardiovascular events, and possible therapeutic options are to increase the dosage, to replace aspirin with another antiaggregant drug or to add another drug. In conclusion, there are many reasons that explain the variability in individual responsiveness to aspirin. The term resistance is probably not exact in describing this phenomenon.

The objective of this study was to investigate the effect of ingestion of powder of hemp seed on blood picture. This study was experienced on five guinea pigs that fed with normal diet (fresh vegetable and tab water), in addition were force-fed 5 g/kg/day of the powder of hemp seed for 60 days by means of an endogastric tube and syringe. At the beginning day and the termination of study day-60 the blood was taken from animals and the erythrocyte number, leukocyte number, packed cell volume (PCV), and hemoglobin concentration values were determined. The result on analysis showed that erythrocyte-count and PCV significantly decreased (p < 0.05) whereas hemoglobin concentration and leukocyte number values showed a steady decline which was not significant (P > 0.05). None of the values fell below the normal physiological range of the experimental animals. This shows that hemp seed which contains tetrahydrocannabinols as its active constituents has long term significant toxicological implication such as bone marrow suppression with respect to the concentration given on the erythrocytes of mammals. It is recommended that individuals who have anemia or immunity complication should not use hemp seed in their food preparation on regular basis.

The recognition that uric acid plays a significant role in cardiac function has been slow to be appreciated. About 50 years ago it was recognized that gout and high uric acid levels were often a marker for coronary heart disease, Since then the literature has contained several hundred studies which have demonstrated a great deal of the physiology of xanthine oxidase inhibition. A reduction in xanthine oxidase improves cardiac output, improves endothelial function, reduces myocardial infarct size, reduces inflammation, reduces myocardial oxidative stress and platelet adhesiveness. It seems logical that these effects would be beneficial to patients with congestive heart failure. A large placebo controlled trial with Allopurinol seems very likely to demonstrate that this old fashioned drug provides a new found benefit.

Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that have ubiquitous cellular functions. In the heart, subclass IA PI3Ks, PI3K-α and beta, regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate myocardial contractility. Loss of p110γ, the catalytic subunit of PI3Kγ, enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum (SR) leading to increased cAMP-mediated phosphorylation of phospholamban. The ability of p110γ to modulate cAMP is likely mediated by the protein-protein interactions with the cAMP-degrading enzymes, phosphodiesterases, independent of its lipid kinase activity. PI3Kγ also plays a key role in modulating the cAMP response and desensitization of beta-adrenergic receptors. Loss of p110γ gamma leads to acute decompensation and rapid progression into heart failure in response to pathological biomechanical stress while lipid kinase-dead mutants were relatively resistant suggesting that elevated intracellular cAMP (and its secondary effects) is an important predisposing factor for heart failure. The commercial availability of specific PI3Kγ inhibitors may be used as therapeutic agents in inflammatory and cardiovascular diseases. In this review article, we discuss the key role of PI3Kγ gamma in regulating cAMP, Ca2+ cycling, β-adrenergic signaling and myocardial structure and function in heart disease.