Current Vascular Pharmacology - Volume 9, Issue 2, 2011

A large number of clinical studies proved definitive effects of angiotensin receptor blocker (ARB) on the prevention of both atherosclerosis and cardiac events improving not only hypertension [1] but also metabolic disorders, such as dyslipidemia, diabetes [2, 3], and metabolic syndrome [4]. In addition, ARBs have been reported to have beneficial cardioprotective effects on improving cardiac hypertrophy, diastolic dysfunction, and cardiac remodeling after myocardial infarction like as angiotensin converting enzyme (ACE) inhibitors [5]. Moreover, ARBs are known for their “beyond blood pressure lowering effects” on end-organ protection, such as renal protection in chronic kidney disease [6, 7], reducing new-onset diabetes [8], prevention for ischemic stroke [9-11], and risk reduction in Alzheimer's disease [12]. To clarify the essential roles of ARBs, we need to understand the multifunctional effects of ARB and make the most of their ability. This special issue of Current Vascular Pharmacology is elaborate concerning atheroprotective effects of ARBs focused on the recent findings related to pleiotropic effects of ARBs. Furthermore, known and proposed mechanisms of how ARBs may improve various proatherogenic conditions are discussed, and these effects may be helpful to explain the mechanisms by which ARBs may improve metabolic disorders. The aim of this special issue of CVP is to remind readers of the evidence-based therapeutic possibility of ARBs and of their clinical relevance. Reviews have been written by forefront experts on data obtained from experimental animal models or clinical studies or both. A variety of excited topics are covered including pleiotropic effects of ARBs on: dyslipidemia (Chapter 1), diabetes mellitus (Chapter 2), vascular metabolism (Chapter 3), vascular endothelial progenitor cells (Chapter 4), metabolic syndrome (Chapter 5), and obesity and gastrointestinal hormones (Chapter 6). In this special issue, we hope these reviews will help both basic and clinical researchers to understand recent ARB-related studies and contribute new concepts of ARB to preventive studies for cardiovascular disease in the future. ACKNOWLEDGEMENTS This work was partly supposed by Grants 21790743 (M.Y.-T.) and 21790744 (to T.T.) from the Ministry of Education, Culture, Science and Technology of Japan.

Angiotensin II type 1 (AT1) receptor blockers (ARBs), widely used in the treatment of hypertension, have cardiovascular, cerebral, and renal protective effects beyond blood pressure control. In addition to direct end-organ protection, some ARBs have been suggested to improve abnormalities of glucose and lipid metabolisms, resulting in an antiatherosclerotic effect in patients with hypertension. In several clinical trials, the effects of ARBs on lipid metabolism have been emerged, although the effects are heterogeneous. Certain subgroups of ARBs such as telmisartan have been identified as partial agonists for the peroxisome proliferators activated receptor (PPAR)-γ, and thus, this class of ARBs has been mostly focused on their effects on lipid metabolism. Based on the pleiotropic effects on lipid metabolism, we can envision that ARBs would provide the promising outcome for hypertensive patients aggregating metabolic risk factors, including dyslipidemia.

Evidence accumulated to date indicates that inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARB) may prevent new-onset of diabetes. ARB is also used for the prevention of occurrence and progression of complications in diabetes and diabetic nephropathy. From the results of recent large-scale clinical studies, ARB is considered as a first choice drug in hypertensive patients with diabetes. In this review article, we focus on the effects of ARB on progression and prevention against diabetes as a metabolic-improving agent.

The renin-angiotensin system (RAS) plays an essential role in fluid and electrolyte homeostasis and the regulation of vascular tone; however, dysregulation and over-activation of the RAS lead to the pathogenesis of various cardiovascular diseases. The RAS is closely associated with NADPH oxidase, a major enzymatic source of reactive oxygen species (ROS) in vasculature, and angiotensin II, the final effecter of the RAS, is a potent stimulator of this oxidase. There are accumulating evidences to support the significance of NADPH oxidase in the pathogenesis of atherosclerosis. We demonstrated that the expression of NADPH oxidase is markedly enhanced in human atherosclerotic coronary arteries, and the distribution of oxidized oxidized low-density lipoprotein (LDL) in vasculature is closely associated with NAPDH oxidase and ROS. Our series of observations indicate there is a vicious circle consisting of vascular NADPH oxidase, the RAS, ROS, and oxidized LDL. Furthermore, we demonstrated that angiotensin II type 1 receptor blockers (ARBs) significantly suppressed the expression of NADPH oxidase p22phox in the aortic walls of patients with thoracic aortic aneurysm. ARBs, widely used for treatment of hypertension and hypertension-related organ damage, have succeeded in reducing the onset of cardiovascular diseases, preventing organ damage, and cardiac death. These beneficial effects of ARBs are largely dependent upon their primary effects of blood pressure lowering. However, this group of agents exerts a wide variety of biological effects on vascular metabolism, including antioxidative and anti-inflammatory actions. These pleiotropic actions play a role in cardiovascular protection. From a viewpoint of oxidative stress, we discuss pleiotropic effects of ARBs on vascular metabolism focusing on pathogenesis of atherosclerosis-based cardiovascular diseases.

Angiotensin II regulates blood pressure and contributes to endothelial dysfunction and the progression of atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) in peripheral blood contribute to postnatal vessel repair and neovascularization. Impaired EPC function in patients with hypertension and diabetes inhibits the endogenous repair of vascular lesions and leads to the progression of atherosclerosis. The number of EPCs in peripheral blood is inversely correlated with mortality and the occurrence of cardiovascular events. Angiotensin II-mediated signaling is implicated in oxidative stress, inflammation and insulin resistance, factors that cause EPC dysfunction. Blockade of the angiotensin II type 1 receptor may therefore present a new therapeutic target for enhancing EPC function.

Metabolic syndrome comprises of a cluster of several risk factors including abdominal obesity, dyslipidemia, elevated blood pressure, and insulin resistance. Many manifestations occur in sequence which is also referred to as the metabolic domino. Because the renin-angiotensin system (RAS) seems to be involved in this domino effect, RAS blockade by angiotensin II receptor blockers (ARB) offers a therapeutic tool for treating hypertension and ultimately the metabolic syndrome itself. In this paper, I describe the effects of ARBs on adiponectin, blood pressure, and fatty liver. Several clinical studies have reported that ARBs elevate adiponectin. ARBs that activate the PPARγ may be more effective than others. In terms of blood pressure, transient ARB administration may prevent the development of hypertension and high doses of ARB may regress mild hypertension. In terms of fatty liver, several research studies have indicated that ARBs may prevent triglyceride accumulation in liver. Again, ARBs that activate PPARγ may be more effective than others. Thus, PPARγ-activating ARBs offer the most hopeful treatment for metabolic syndrome. Further studies are needed to confirm this hypothesis.

Obesity is strongly associated with type 2 diabetes, hypertension, and hyperlipidemia, which is one of the leading causes of mortality and morbidity worldwide. It is now clear that gut hormones play a role in the regulation of body weight and represent therapeutic targets for the future treatment of obesity. Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, but also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Importantly, blockade of the RAS attenuates weight gain and adiposity by enhanced energy expenditure. The favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. Treatment with telmisartan or losartan significantly reduced the development of lipid-rich plaque. However, treatment with telmisartan significantly improved endothelial dysfunction and inhibited lipid accumulation in the liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPAR-γ, beyond its blood pressure-lowering effect, through Ang II blockade, which may be called “metabosartan”.

Synthetic grafts, namely expanded polytetrafluoroethlene (ePTFE) and poly(ethylene terephthalate) (Dacron), used for cardiovascular bypass surgery are thrombogenic. Lining the inner lumen (“seeding”) of synthetic grafts with endothelial cells (ECs) increases patency rates similar to those of autologous grafts (e.g. saphenous vein). The major drawback with seeding grafts is the retention of cells present on the graft after implantation in vivo, where large portions of cell wash off. Preconditioning the seeded EC monolayer with shear stress has been shown to promote the reorganisation of the EC cytoskeleton and production of extracellular matrix, resulting in higher EC retention after exposure to blood flow. Vascular ECs have a number of essential and complex roles. ECs synthesise and secrete vasoconstrictors, vasodilators, growth factors, fibrinolytic factors, cytokines, adhesion molecules, matrix proteins and mitogens that modulate many physiological processes such as wound healing, haemostasis, vascular remodelling, inflammatory and immune responses. Vascular cells in vivo are exposed to haemodynamic forces created by the pulsatile flow of blood through the vessel. Due to their unique anatomical position, ECs are constantly exposed to shear stress forces and allow the vessel wall to adapt to changes by modulating EC structure and function. This review describes the mainly in vitro and in vivo studies used to define the molecular role haemodynamics have in vascular disease and its usage in developing tissue engineered vascular bypass grafts.

Inflammation plays a role at all stages of atherosclerosis. Neopterin, a pteridine mainly synthesized by activated macrophages, is a marker of inflammation, immune system activation and an active participant in cardiovascular disease. Measurement of neopterin levels may help follow the evolution of specific inflammatory conditions (e.g. viral infection, renal transplant rejection, systemic inflammatory diseases, nephritic syndrome and autoimmune diseases). Serum levels of neopterin are elevated also in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Moreover, plasma levels of this molecule might predict adverse cardiovascular events in patients with CAD, acute coronary syndromes or severe PAD. In addition, neopterin levels are related to the development of heart failure. We provide an updated overview on neopterin and, its links with CAD, left ventricular dysfunction, and PAD. We also describe its potential role in cardiac regenerative strategies with using bone marrow cells.

Hypocholesterolemia is defined as total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels below the 5th percentile of the general population adjusted for age, gender and race. Hypocholesterolemia may be attributed to inherited disorders or several secondary causes. Inherited forms of hypocholesterolemia consist of a group of rare diseases. The best studied are familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL). Clinical diagnosis rests on lipid levels and the pattern of inheritance after secondary causes are excluded. Patients with primary hypobetalipoproteinemias may manifest a variety of symptoms and signs affecting several organs (steatorrhea, neurological and ophthalmological symptoms, non-alcoholic fatty liver disease) or be asymptomatic. Understanding hypocholesterolemia and the underlying molecular basis is of crucial importance since this may provide new insights in the treatment of hypercholesterolemia and cardiovascular disease.

Systemic Sclerosis (SSc) is a complex multisystem disease characterized by vascular involvement and generalized disturbance of the microcirculation. Pulmonary vascular disease leads to systemic sclerosis-related pulmonary arterial hypertension (SScPAH). SScPAH is a devastating complication with a considerable impact on prognosis, being a common cause of disease-related death. The ability to detect this process at an early stage by simple means would be of great value, since effective treatment is now available. There is increasing evidence that several biomarkers increase in proportion to the extent of right ventricular dysfunction and correlate with hemodynamic, echocardiographic and functional measurements of pulmonary vascular disease. Biomarkers may be used to identify high-risk patients for more invasive procedures, provide prognostic information, and guide vasodilator therapy. In this article, we review potential biomarkers in SScPAH as tools for screening, diagnostic evaluation, risk stratification, prediction of disease severity and indicators of treatment efficacy.

Epidemiologic studies have demonstrated that increased high-density lipoprotein cholesterol (HDL-C) is a protective factor against cardiovascular disease. However, the beneficial therapeutic effects of raising HDL-C are proving difficult to confirm in humans. Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms. A new approach was developed to measure in vivo RCT from labeled cholesterol macrophages to liver and feces in mice. Since its original publication, this method has been extensively used to assess the effects of genetic manipulation of pivotal genes involved in HDL metabolism on this major HDL antiatherogenic function in mice. These studies indicate that in vivo macrophage-specific RTC is a strong predictor of atherosclerosis susceptibility compared with steady-state plasma HDL-C levels or other global RCT measurements. This review aims to identify the best molecular targets for improving this HDL antiatherogenic function. Strong evidence supports a positive effect of interventions on macrophage adenosine triphosphate-binding cassette transporter (ABC) A1 and neutral cholesteryl ester hydrolase, apolipoprotein (apo) A-I, macrophage apoE, liver scavenger receptor class B type I and ABCG5/G8 on in vivo macrophage-specific RCT and atherosclerosis susceptibility. However, other genetic modifications have yielded conflicting results. Several preclinical studies tested the effects on macrophage-specific RCT in vivo of promising new HDL-based therapeutic agents, which include cholesteryl ester transfer protein inhibitors, apoA-I-directed therapies, liver X receptor and peroxisome proliferator-activated receptor agonists, intestinal cholesterol absorption inhibitors, fish oil and phenolic acid intake, inflammatory modulation and non-nucleoside reverse transcriptase inhibitors. This review also discusses recent findings on the potential effects of these therapeutic approaches on macrophage RCT in mice and cardiovascular risk in humans.

Nephroangiosclerosis (NAS) is a major cause of progressive renal insufficiency. Hypertension is very important in the causation of NAS but other factors such as race, age, metabolic variables, and genetics play a pathogenic and prognostic role. A multifactorial treatment strategy, including antihypertensive, lipid-lowering and anti-platelet agents, could improve cardiovascular and renal outcomes in patients with vascular nephropathy.

Cardiovascular disease, in spite of the significant interventions that have been made for primary and secondary preventions, is still the main cause of death in men and women in the western world. The prevalence of myocardial infarction in women with normal level of estrogens is very rare and 3-5 times lower than in men. However, this favorable relationship disappears in older women. Thus, the results from several clinical trials regarding the hormone status of women and the occurrence of cardiovascular events have led to the conclusions that estrogens exert a protective effect on atherogenesis, on formation of the atherosclerotic plaque, and, subsequently, on clinical manifestations of atherogenesis. In the last years, after the development of models for studying atherogenesis significant progress has been made, concerning the understanding of evolutionary biological and cellular events, leading to atherogenesis. In this review, atherogenesis (the formation of atherosclerotic plaque and its stages), the factors which advance atherogenesis (environmental and genetic), the effect of estrogens on the stages of atherogenesis, and the effect of estrogens on the factors which promote atherosclerosis will be discussed. Finally, hormone replacement therapy will be briefly described.