Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 4, Issue 3, 2006

Hypoxia inducible factor-1 (HIF-1) is a central component of the oxygen sensing system that coordinates cellular responses to conditions of decreased oxygen availability. The hypoxia inducible transcription factor HIF-1 is a heterodimer composed of the helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) proteins HIF-1alpha and the aryl hydrocarbon nuclear translocator (ARNT) also known as HIF-1beta. Transactivation of HIF-1 transmits a hypoxic signal into pathophysiological responses such as angiogenesis, erythropoiesis, vasomotor control, an altered energy metabolism, as well as cell survival decisions by regulating a staidly growing number of target genes. Among recent advances are the discoveries that cytokines and growth factors make use of the 'hypoxic signaling system' under normoxia. Here we summarize current knowledge and existing concepts that help to understand how cytokines and hormones affect protein accumulation of HIF- 1alpha and discuss potential implications of activating HIF-1 under normoxia. Considering the fundamental role of cytokines during inflammation may predict a role of HIF-1alpha in coordinating cellular responses to pathogens and point to the connection of cancer and inflammation. Moreover, we will address potential feed-back mechanisms showing an impact of HIF-1 on cytokine production. These considerations suggest an intimate signaling cross-talk between cytokines and the HIF-1 system.

The aims of the present review are to summarize and to discuss the role of hypoxia-inducible factor-1 (HIF-1) and the expression and functions of vasoactive substances in chronic hypoxemia with specific focus in the liver and the carotid body. Vascular remodelling and vasoactive substances play important functional roles in the adaptive response to chronic hypoxemia for the maintenance of oxygen homeostasis in all systems in man. HIF-1 regulates the gene expression of vasoactive substances such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and enzymes for producing nitric oxide (NO). Recent studies have shown the effect of chronic hypoxia on the expression of HIF-1α and HIF-1-target genes in multiple organ systems including the liver and the carotid body. Results are consistent with increases in the hematocrit levels, pulmonary arterial pressure and right heart mass developed during chronic hypoxia. In addition, the carotid body is also hyperplastic and increases in organ mass with increased levels of HIF-1α and the vasoactive substances. These molecules increase the mitotic activity and modulate the excitability of the chemoreceptor. Intriguingly, the liver morphology, serum alanine aminotransferase and 8-isoprostane levels are within normal range in chronic hypoxia, suggesting the absence of significant oxidative stress. Yet, the HIF-1α is upregulated and the mRNA and protein levels of VEGF, ET-1, inducible and constitutive NO synthases are elevated in the liver during chronic hypoxia. In conclusion, the adaptive response to long-term hypoxemia involves compensatory mechanisms mediated by expressing significant levels of HIF-1α and vasoactive substances regulated by HIF-1.

The renin-angiotensin-aldosterone system (RAAS) plays a relevant role not only in the pathophysiology of essential hypertension, but also in the development of hypertensive target organ damage. Different drugs acting on RAAS components are now available: angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II AT1 receptors blockers (ARBs), non-selective and selective aldosterone antagonists. The review will focus on their effects on hypertensive organ damage. In fact, apart from the well known efficacy in reducing blood pressure, all these drugs have been demonstrated to protect against target organ damage, reversing or preventing its development. The main issues addressed will be: effects of the RAAS blockade on heart and kidney disease, protective action against arterial wall damage, with a focus on the endothelial protection. The comparison among ACE inhibitors, ARBs and aldosterone antagonists will be discussed, with specific reference to different class and/or drug effects and to the results of few studies evaluating the effects of combination therapy with different drugs blocking the RAAS.

Interleukin (IL)-1 is a pro-inflammatory cytokine and a central mediator in the cytokine network, and is known to control important functions both in the immune system and inflammation. The activity of IL-1 is counter-regulated by its endogenous inhibitor, IL-1 receptor antagonist (IL-1Ra). IL-1 and IL-1Ra are produced and secreted by a variety of cells including those responsible for controlling immunity. A recent study indicated that IL-1 and IL-1Ra transcripts were expressed in the vessel wall, suggesting that these cytokines contribute to the development and progression of vascular diseases. In this review, we will discuss the recent advances in our understanding of the mechanism of action of IL-1 in occlusive arterial diseases such as neointimal hyperplasia and atherosclerosis, specifically in a mouse model.

In vitro and ex vivo interactions of betaadrenoceptor blocking drugs, antihistamines and chloroquine with blood platelets and polymorphonuclear leukocytes resulted in different alterations of regulatory functions of these blood cells. Inhibition of platelet aggregation, arachidonate regulatory pathway, 5-hydroxytryptamine transportation, removal of platelet membrane receptors, inhibition of second messenger pathways at subcellular level and suppression of phagocytosis are indicative of nonreceptor rather than specific receptor interactions. Binding of drugs with biomembranes is reversible depending on the ionic charge of the molecule and hydrophobicity of the bilayer, partition coefficient, pH and pKα of the amphiphilic molecules and other physico-chemical properties of amphiphilic drugs. Alterations in the drug molecule structure alters the drug-phospholipid binding profile. Any change in the metabolism of membrane phospholipids directly or indirectly influences one or more of the important components of the phospholipid-signalling pathway. In addition to changes in phospholipase A, C and D activities, protein kinase C, calmodulin-phosphodiesterase, Ca2+,Mg2+-ATPase, Na+,K+-ATPase and other messengers were found to be changed in cells and tissue after cationic amphiphilic drug (CAD) administration. Although not much has been understood of the mechanism by which some CAD affect immune functions, there are good reasons to suggest that these effects might occur. CADs share sufficient similarities in their structure even though they come from diverse pharmacological classes. CADs affect ion transport, immune functions, tumour growth, serotonin metabolism and several other functions in the body. Extensive therapeutic use and associated side effects have generated a great deal of interest in understanding the nonreceptor interactions with CADs.

The role of individual fatty acids in blood pressure regulation is unclear, although it is known that the modifications in the levels of fatty acids in the diet are able to change the entire profile of fatty acids as well as cholesterol levels in cellular membranes. These chemical changes are accompanied by changes in the physiological state of the cellular membranes and have suggested an influence on cellular metabolism and of course, on the regulatory processes. Local and circulating renin-angiotensin-systems (RAS) are examples of systems that may be involved in the pathogenesis of hypertension. Angiotensin II (AngII) has been considered as the main effector peptide of the RAS, but other peptides derived from the metabolism of AngII, as angiotensin III (AngIII) and angiotensin IV (AngIV) have shown to play significant roles. This review will briefly summarize what is known about the effects of fatty acids, cholesterol and other related compounds on the activity of the aminopeptidases involved in the metabolism of Ang II and AngIII. We conclude that these enzyme activities may be modified in different way, and therefore, possible modifications in RAS and in cardiovascular illness may be possible too.