Current Vascular Pharmacology, Vol. 2, No. 4, 2004
Contents
Non-Lipid
Effects of Statins: Emerging New Indications Pp.309-318
Aylin Yildirir and Haldun Muderrisoglu
Inhibition
of the Tissue Factor Coagulation Pathway Pp.319-327
Paolo Golino, Lavinia Forte and Salvatore De Rosa
23Na
Magnetic Resonance Imaging for the Determination of Myocardial Viability: The
Status and the Challenges Pp.329-333
Michael Horn
Antioxidant
Therapy in Diabetic Complications: What is New? Pp.335-341
Roberto Da Ros, Roberta Assaloni and Antonio Ceriello
The
Role of Diffusion- and Perfusion-Weighted Magnetic Resonance Imaging in Drug
Development for Ischemic Stroke: From Laboratory to Clinics Pp.343-355
Turgut Tatlisumak, Daniel Strbian, Usama Abo Ramadan and
Fuhai Li
Regulation
of Hemostasis by Singlet-Oxygen (1DO2*) Pp.357-362
Thomas W. Stief
Possible
Non-Classic Intracellular and Molecular Mechanisms of LDL Cholesterol Action
Contributing to the Development and Progression of Atherosclerosis Pp.363-370
Ioanna Gouni-Berthold and Agapios Sachinidis
Mechanisms
of Cardiovascular Changes in an Experimental Model of Syndrome X and
Pharmacological Intervention on the Renin-Angiotensin-System Pp.371-377
Roberto Miatello, Montserrat Cruzado and Norma Risler
Vascular
Stiffness: Measurements, Mechanisms and Implications Pp.379-384
Yi-Xin Wang and Richard M. Fitch
Angiotensin
II, Cell Proliferation and Angiogenesis Regulator: Biologic and Therapeutic
Implications in Cancer Pp.385-399
Elizabeth Escobar, Tatiana Sofía Rodriguez-Reyna, Oscar
Arrieta and Julio Sotelo
Abstracts
[Back to top] Non-Lipid
Effects of Statins: Emerging New Indications
Aylin Yildirir and Haldun Muderrisoglu
Statins are beneficial both in the primary and secondary prevention of atherosclerotic vascular disease and acute events in a broad spectrum of patient subgroups. However, the observed clinical benefit with statin therapy is much greater than expected through the reduction of cholesterol levels alone. Clinical and experimental studies suggested that several antiatherosclerotic effects other than lipid lowering also contribute to the observed benefit of statin therapy. These ‘pleiotropic effects’ include improvement of endothelial function, antitrombotic actions, plaque stabilization, reduction of the vascular inflammatory process and anti-oxidation. Statins may also exhibit a wide variety of actions other than antiatherosclerotic effects. Recent observational data documented a potential association between statin use and improvement of fracture risk in osteoporosis. Despite the lack of randomized trials, epidemiological and limited clinical data suggested that statins might retard the pathogenesis of Alzheimer’s disease. Observational data indicated that the progression of aortic stenosis and valvular calcification might be delayed in statin users. In addition, the deterioration of congestive heart failure may be delayed with statins via anti-inflammatory, vascular endothelial and antiatherosclerotic actions. Furthermore, preliminary clinical studies suggested that, by their immunosuppressive actions statins might reduce the incidence of rejection following organ transplantation. Currently, there is not enough evidence to prescribe therapy for such patients. However, ongoing studies are exploring the role of statin therapy for these new indications. This review will discuss several non-lipid effects of statin therapy currently under investigation.
[Back to top] Inhibition of the Tissue Factor Coagulation Pathway
Paolo Golino, Lavinia Forte and Salvatore De Rosa
It is widely accepted that blood coagulation in vivo is initiated during normal hemostasis, as well as during intravascular thrombus formation, when the cell-surface protein, tissue factor, is exposed to the blood as a consequence of vascular injury. In addition to its essential role in hemostasis, tissue factor may be also implicated in several pathophysiological processes, such as intracellular signaling, cell proliferation, and inflammation. For these reasons, the tissue factor:factor VIIa complex has been the subject of intense research focus. Many experimental studies have demonstrated that inhibition of tissue factor:factor VIIa procoagulant activity are powerful inhibitors of in vivo thrombosis and that this approach usually results in less pronounced bleeding tendency, as compared to other “more classical” antithrombotic interventions. Alternative approaches may be represented by transfecting the arterial wall with natural inhibitors of tissue factor:factor VIIa complex, such as tissue factor pathway inhibitor, which may result in complete inhibition of local thrombosis without incurring in potentially harmful systemic effects. Additional studies are warranted to determine the efficacy and safety of such approaches in patients.
[Back to top] 23Na Magnetic Resonance Imaging for the
Determination of Myocardial Viability: The Status and the Challenges
Michael Horn
The determination of the extent of the non-viable tissue after myocardial infarction has a major impact on further treatment of patients. During acute myocardial infarction, total sodium content of the tissue is elevated. This is caused by discontinuation of ion homeostasis, edema formation and membrane rupture. The situation is a different one in the chronic phase of scar formation, where cell migration causes changes in the ratio of extra- and intracellular volume. The accumulation of sodium causes an increase in the signal in 23Na magnetic resonance imaging. The differences in intra- and extracellular sodium concentration modulate total sodium content and can be used as a natural, intrinsic contrast. In animal experiments, 23Na magnetic resonance imaging allows the non-invasive determination of infarct size. As neither stunned nor hibernating tissue shows elevated total sodium content of the tissue, the method is able to discriminate viable and non-viable tissue. A small number of initial clinical studies show promising results for the use of this technique in humans. The development of 23Na magnetic resonance imaging and the current status of the application are described.
[Back to top] Antioxidant Therapy
in Diabetic Complications: What is New?
Roberto Da Ros,
Roberta Assaloni and Antonio Ceriello
In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolysis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. Classic antioxidants, like vitamin E, failed to show beneficial effects on diabetic complications probably due to their only “symptomatic” action. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Statins increase NO bioavailability and decrease superoxide production, probably interfering with NAD(P)H activity and modulating eNOS expression. ACE inhibitors and AT-1 blockers prevent hyperglycemia-derived oxidative stress modulating angiotensin action and production. This effect is of particular interest because hyperglycemia is able to directly modulate cellular angiotensin generation. Calcium channel blockers inhibit the peroxidation of cell membrane lipids and their subsequent intracellular translocation. Thiazolinediones bind and activate the nuclear peroxisome proliferator-activated receptor gamma, a nuclear receptor of ligand-dependent transcription factors. The inhibition of this receptors lead to inhibition of the inducible nitric oxide synthase and consequently reduction of peroxynitrite generation. This preventive activity against oxidative stress generation can justify a large utilization and association of this compound for preventing complications in diabetic patients, where antioxidant defences have been shown to be defective.
[Back
to top] The Role of Diffusion- and
Perfusion-Weighted Magnetic Resonance Imaging in Drug Development for Ischemic
Stroke: From Laboratory to Clinics
Turgut Tatlisumak,
Daniel Strbian, Usama Abo Ramadan and Fuhai Li
Ischemic stroke is a major cause of mortality and morbidity in industrialized countries and is almost always caused by occlusion of a cerebral artery by a clot. As the reversibly injured brain tissue evolves into irreversible infarction within a short period of time after onset of ischemia, it is extremely important and urgent to reverse the serious consequences of brain ischemia in the hyperacute phase when the ischemic brain tissue is still salvageable. Numerous thrombolytic and potentially neuroprotective agents have been studied in stroke patients with little success as the only approved therapy is thrombolysis with recombinant tissue plasminogen activator (r-tPA) within 3 h of stroke onset in highly selected patients (approximately 5 to 10 % of all acute stroke patients). One major obstacle in the development of effective therapies for ischemic stroke has been the lack of versatile imaging techniques. New magnetic resonance imaging (MRI) modalities, specially diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) have been used in experimental studies with great success for over a decade and now are gradually entering clinical use. DWI and PWI can detect brain ischemia in the early phase in its full extent thus ensuring a definite diagnosis, allowing for follow-up of the ischemic lesion size over time with good spatial and temporal resolution, demonstrating perfusion deficit and reperfusion and the existence and the extent of penumbra while only requiring a few minutes of imaging time. DWI and PWI do not just give us the correct diagnosis of ischemic stroke, but allow us to acquire in vivo lesion size before therapeutic regimen is started and monitor the therapeutic efficacy thereafter, thus overcoming the potential pretreatment bias. We used DWI and PWI to evaluate novel therapeutic approaches for ischemic stroke in numerous experimental studies and lately in humans. With DWI and PWI, we are able to determine the in vivo efficacy (or lack of efficacy) of new therapeutic regiments (both neuroprotective and thrombolytic agents, or combination therapies) in a rapid, safe, and reliable way and in a relatively small number of well-selected, well-defined, and homogeneous patients. This approach may, therefore, significantly accelerate the development of new remedies for stroke patients.
[Back to top] Regulation
of Hemostasis by Singlet-Oxygen (1DO2*)
Thomas W. Stief
Hemostasis is the system of generation and destruction of thrombi. It consists of coagulation and thrombolysis and has a plasmatic part and a cellular one, the latter being the thrombocytes and endothelial cells for coagulation and the polymorphonuclear granulocytes (PMN) for thrombolysis. Main products of PMN are oxidants of the hypochlorite/chloramine-type that can generate the nonradical excited oxidant singlet molecular oxygen (1DO2*). Physiologically, 1DO2* reacts with methionine and cysteine residues and with carbenic structures in lipids, generating dioxetanes, which upon disruption emit photons in the blue spectrum of light (380-450 nm). It modifies some important hemostasis components in blood: 1DO2* inactivates the factors I (fibrinogen), V, VIII, vWF, X, plasminogen activator inhibitor-1 (PAI-1), and a2-antiplasmin. 1DO2* oxidation of plasminogen and fibrin facilitates their specific cleavage by plasminogen activators and plasmin. Furthermore, 1DO2* downregulates thrombocyte-function and upregulates PMNfunction. Chloramines seem to be the main physiologic generators of 1DO2* : in concentrations of 0.1-2 mM in blood they strongly inhibit coagulation and enhance thrombolysis. The biogenesis and reaction pattern of 1DO2* is of importance to understand the PMN-physiology in hemostasis, giving rise to new therapy forms of thromboatherothrombosis in man.
[Back to top]
Possible Non-Classic Intracellular and Molecular Mechanisms
of LDL Cholesterol Action Contributing to the Development and Progression of
Atherosclerosis
Ioanna Gouni-Berthold and Agapios Sachinidis
Elevated low density lipoprotein (LDL) cholesterol (LDL-C) levels represent one of the most important risk factors for atherosclerosis and therefore cardiovascular morbidity and mortality. LDL-C operates at different levels and through various classic and non-classic mechanisms. For example, it has been recently shown that both native and oxidized LDL are potent growth factors for several cell types such as vascular smooth muscle cells (VSMC) participating in the development and progression of atherosclerosis. Moreover, LDL-C modulates the expression of various growth factors and growth factor receptors that are involved in the process of atherosclerosis. More specifically, LDL-C can phosphorylate and therefore activate the epidermal growth factor (EGF) receptor and enhance the production of platelet derived growth factor (PDGF)-AA and of the PDGF receptors. LDL as well as oxidized LDL (oxLDL) signal transduction pathways involve trimeric G-proteins and cAMP, protein kinase C and ceramide, diacylglycerol and inositol-1,4,5- triphosphate, Ca+2, Na+/H+ exchange, c-fos and egr-1, phospholipases C, A2 and D, Raf-1, MEK1/2, the ERK1/2 (p42/44), SAP/JNK and p38 isoforms of the mitogen activated protein kinases (MAPK) as well as the signal transuding element gp 130. Furthermore, the mitogenic effects of oxLDL may be mediated by its oxidation products such as lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA), through LDL-induced lactosylceramide (LacCer) synthesis, and, as our group has recently shown, through LDL-adherent factors such as sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC).
We review the various LDL-mediated signal transduction pathways implicated with the development and progression of atherosclerosis.
[Back to top]
Mechanisms of Cardiovascular Changes in an Experimental Model
of Syndrome X and Pharmacological Intervention on the Renin-Angiotensin-System
Roberto Miatello, Montserrat Cruzado and Norma Risler
Various cardiovascular risk factors and disease states similar to those present in type 2 diabetic patients also seem to be present in non-diabetic individuals. This cluster of risk factors has been called syndrome X, also known as metabolic cardiovascular syndrome or insulin resistance syndrome. Vascular wall components changes, including endothelial dysfunction and vascular smooth muscle cell (VSMC) migration and proliferation, could be involved in the cardiovascular alterations associated with this state.
Fructose fed rats (FFR) provide a model of dietary-induced insulin resistance, which has been used to assess the pathophysiological mechanisms of the metabolic and cardiovascular changes associated to the syndrome X. FFR have hyperinsulinemia, insulin resistance (altered glucose tolerance test) and hypertriglyceridemia; they also develop moderate hypertension and cardiac hypertrophy. This has been confirmed in male rats of different strains, such as Wistar and Sprague-Dawley, chronically fed with a 60% fructose-chow or 10% fructose in the drinking water. At different levels of the cardiovascular system, FFR exhibit changes in the nitric oxide generation system and in primary cultured proliferation of VSMC from conduit and resistance arteries. These abnormalities were normalized by long-term treatment with pharmacological agents acting on the renin-angiotensin system (RAS), such as angiotensin converting-enzyme inhibitors or angiotensin-AT1 receptor antagonists, that also lowered blood pressure to control levels and reversed cardiac hypertrophy.
Evidence suggests an important role for the RAS in the pathogenic mechanisms involved in this model of syndrome X. Furthermore, beneficial pharmacological intervention seems to be mediated by AT2 receptors and kinins.
[Back to top]
Vascular Stiffness: Measurements, Mechanisms and Implications
Yi-Xin Wang and Richard M. Fitch
Aging is the dominant process altering vascular stiffness. Risk factors for cardiovascular disease, such as smoking, hypertension and diabetes mellitus, mediate their effects by altering the structure, properties, and function of the vascular wall and endothelial components. Increased vascular stiffness exerts greater afterload stress on the heart. The ability to detect and monitor changes in the physical properties of arteries holds potential to intervene for prevention or attenuation of disease progression. Pulse wave velocity has been used as an index for vascular stiffness and as a surrogate marker for atherosclerosis in laboratory animal models and in the clinic. Mouse models have been used extensively in vascular research. We and others have developed invasive and noninvasive methods to measure pulse wave velocity in rodents, such as rats and mice.
Here we review the evidence that the development of atherosclerosis contributes greatly to vascular stiffening; that endothelial nitric oxide plays an important role in modulating vascular stiffness; that angiotensin II injures the vessel and increases vascular stiffness; and that treatment with estrogen attenuates vascular inflammation and reduces vascular stiffness. In addition, we also discuss the influence of hemodynamic, metabolic, inflammatory stimuli in impairing arterial wall integrity as well as potential mechanisms modulating vascular stiffness.
[Back to top]
Angiotensin II, Cell Proliferation and Angiogenesis Regulator: Biologic and
Therapeutic Implications in Cancer
Elizabeth Escobar, Tatiana Sofía Rodriguez-Reyna, Oscar Arrieta and Julio Sotelo
Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT1 and AT2) are the most important. Stimulation of AT1 leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT2 receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT1. The stimulation of AT1 activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor b and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In addition, the AT1 receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications.