Current Vascular Pharmacology - Volume 1, Issue 1, 2003

Despite advances in immunosuppressive drugs, coronary artery transplant vasculopathy (CATV) is the major cause of graft failure that limits long-term survival of cardiac transplantation. The pathogenesis of CATV involves a chronic immune response of the recipient to the donor vasculature in which activated recipient immune cells damage the endothelium and produce cytokines, resulting in vascular smooth muscle cell (VSMC) activation. Activated VSMC migrate from the media into the lumen, proliferate, and elaborate cytokines and matrix proteins, resulting in loss of lumen diameter and vascular contractility. Because of its extensive nature, interventions which are successful in patients with conventional coronary artery disease are often not applicable to the majority of patients with CATV. Although intended for immune suppression, many immunosuppressive agents owe at least part of their efficacy to their anti proliferative effects on VSMC, including rapamycin, mycophenolic acid, cyclosporin, calcium channel blockers, and HMG CoA reductase inhibitors. Because activation of VSMC is responsible for most of the obliterative arterial intimal thickening present in solid organ allografts, the induction of expression of a selected set of genes may reflect the status of acceptance of the vasculature by the recipient, and the activation, migration, and proliferation of VSMC represent potential points for therapeutic intervention. The risk of infection and malignancy associated with immunosuppressive therapy further promote the need to identify a molecular target which directly modulates the VSMC response to injury. This review will summarize the anti proliferative effects that immunosuppressive drugs have on VSMC proliferation. We will also describe efforts to define the genes which regulate the vascular response to allograft injury, and describe how some of these proteins may represent targets to reduce VSMC proliferation and attenuate CATV.

Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoprotein such as very low density lipoproteins and chylomicrons.A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and decrease in high density lipoprotein (HDL) cholesterol. The increase in plasma TG and decrease in HDL cholesterol are risk factors of coronary heart disease. However, whether LPL directly or indirectly promotes or protects against atherosclerosis remains unclear as two contrary views exist in this regard: one where LPL promotes atherosclerosis and one where LPL protects against atherosclerosis.Many studies have been carried out to investigate whether LPL is an anti-atherogenic or atherogenic enzyme by using animals with genetic defects or with an excess of this enzyme. From these studies, much evidence has been acquired showing that LPL is an anti-atherogenic enzyme.We hypothesized that elevating LPL activity would cause a reduction of plasma TG and increase in HDL cholesterol, resulting in protection against the development of atherosclerosis. To test this hypothesis, we studied the effects of the LPL activator NO-1886 in animals.NO-1886 has been shown to increase LPL mRNA in adipose tissue and myocardium, and increase LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 has also been shown to decrease plasma TG levels accompanied by a concomitant rise in HDL cholesterol. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortae. The results of multiple regression analysis in these studies suggest that the increase in plasma HDL cholesterol and the decrease in TG protect against atherosclerosis. We have determined in our studies that the atherogenic lipid profile is changed to an anti-atherogenic lipid profile by increasing LPL activity, resulting in protection against the development of atherosclerosis. Therefore, we believe that high activity of LPL is antiatherogenic, whereas a low activity of LPL is atherogenic.

A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kB (NF-kB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.

Bladder outlet obstruction (BOO) is a common disorder that is associated with urinary tract symptoms. Nitric oxide (NO), synthesized by NO synthase (NOS) is a potent vasodilator that is present throughout the urinary tract and the corpus cavernosum. Endothelin-1 (ET-1) conversely is a potent vasoconstrictor peptide that is similarly distributed throughout the urinary tract. ET-1 and NO as well as possessing opposing actions regulate each other's synthesis. The disruption of the balance between ET-1 and NO is associated with various vascular pathologies. However, their potential roles in the pathogenesis of urinary tract disorders, secondary to BOO, is not well established.New Zealand White rabbits with BOO are considered to be a suitable model of the human condition. Hence, using this model, we systematically investigated the potential roles of ET-1 and NO in the pathogenesis of the various urological disorders associated with BOO.In this review we discuss the results of our studies, which support the concept that an imbalance between ET-1 and NO may be associated with the pathogenesis of urinary tract disorders secondary to BOO. We also discuss the potential clinical implications of this association.This review is based on the Bard Silver Medal Lecture given (by MAK) at the 2002 British Association of Urological Surgeons (BAUS) annual meeting.

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.

The vascular wall is an integrated functional component of the circulatory system that is continually remodelling or is developing atherosclerosis in response to hemodynamic or biomechanical stress. In this process mechanical force is an important modulator of Vascular Smooth Muscle Cell (VSMC) morphology and function, including apoptosis, hypertrophy and proliferation that contribute to the development of atherosclerosis, hypertension, and restenosis. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. It has been demonstrated that mechanical stress rapidly induces phosphorylation of the platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once the mechanical force is sensed, protein kinase C and Mitogen Activated Protein Kinases (MAPKs) were activated, leading to increased transcription factor activation. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signaling pathways, usually used by growth factors. Based on the progress in this field, this article attempts to formulate a biomechanical stress hypothesis, i.e. that physical force initiates signal pathways leading to vascular cell death and inflammatory response followed by VSMC proliferation. These findings have provided promising information for designing new drugs or genes for therapeutic interventions for vascular diseases.

During the past 20 years, the proteins of the “contact system”, namely high molecular weight kininogen (HK), kallikrein and Factor XII have been shown to have very little direct impact on hemostasis despite their initial description as initiators of the “intrinsic system”. In fact these proteins have rather anticoagulant and profibrinolytic properties. The focus of this review is to summarize the known antithrombotic properties of HK demonstrating its potential application for the novel therapeutic interventions against thromboembolic complications. In particular, HK can inhibit platelet aggregation, as (i) its domain 5 interferes with ligand binding of αIIbβ3-integrins, (ii) its domain 3 blocks thrombin-dependent platelet aggregation by interfering with thrombin binding to the glycoprotein Ib-IX-V complex on platelets, (iii) bradykinin, which is derived upon cleavage of HK, blocks thrombin-induced platelet aggregation, and (iv) HK domain 2 can inhibit the function of platelet calpain. Moreover, HK may have profibrinolytic actions as it can (i) inhibit plasminogen activator inhibitor-1 function and (ii) potentiate prourokinase activation with subsequent pericellular plasmin formation. Indeed, patients lacking circulating HK are at increased risk for thrombosis, and a prothrombotic phenotype was reported for kininogendeficient rats. All these observations render kininogen antithrombotic, rather than prothrombotic, and the ongoing research aims to develop novel kininogen-related antithrombotic therapies.

Several evidences, ranging from in vitro experiments, pathologic analysis and epidemiologic studies, show that atherosclerosis is intrinsically an inflammatory disease. The plasma concentrations of interleukin-6 (IL-6) and its hepatic by-product, C-Reactive Protein (CRP), appear to reflect the intensity of occult plaque inflammation and by inference may determine the vulnerability of plaque rupture. The monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in initiating coronary artery disease by recruiting monocytes/macrophages to the vessel wall. This leads to the formation of atherosclerotic lesions and also increases the vulnerability of the plaque. Indeed, circulating IL-6 and MCP-1 levels are elevated in patients with acute myocardial infarction, and also in patients with unstable angina, but not in those with stable angina. The plasma IL-6 and MCP-1 concentrations are also increased after percutaneous coronary intervention (PCI), and late restenosis is correlated with an increase in IL-6 or MCP-1 concentrations after the procedure. This finding suggests that the expression of IL-6 and MCP-1 may not only be related to the instability of atheromatous plaques, but also to the formation of restenotic lesions after PCI. The development of drugs specifically targeted against IL-6 and MCP-1 may be useful in the prevention of plaque formation, myocardial infarction and restenosis.

Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine, 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, the 5-HT1B / 1D / 1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D / 5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side effects.

Excessive cellular proliferation contributes to the pathobiology of vascular obstructive diseases (e.g., atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure). Therefore, anti-proliferative therapies may be a suitable approach in the treatment of these disorders. Candidate targets for such strategies include the cyclin-dependent kinase / cyclin holoenzymes, members of the cyclin-dependent kinase family of inhibitory proteins, tumor suppressors, growth factors and transcription factors that control cell cycle progression. In this review, we will discuss the use of pharmacological agents and gene therapy approaches targeting cellular proliferation in animal models and clinical trials of cardiovascular disease.

At homeostasis, vascular cells display a very low proliferative rate and a scant migratory activity. However, hyperplastic growth and locomotion of vascular cells are a hallmark of vascular remodeling during several pathophysiological conditions (e. g., neovascularization, arteriosclerosis and restenosis post-angioplasty). Thus, a better understanding of the molecular mechanisms that control vascular cell proliferation and migration should facilitate the development of novel therapies to treat cardiovascular disease. In this review, we will discuss recent studies implicating the cell cycle regulatory protein p27Kip1 as a key modulator of vascular cell growth and locomotion in vitro and during vascular remodeling in vivo.