Current Pharmaceutical Design - Volume 19, Issue 17, 2013

The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of vasoconstriction, cardiovascular hypertrophy and hyperplasia. Two distinct subtypes of Ang II receptor, type 1 (AT1) and type 2 (AT2), have been identified, and both have been shown to belong to the G protein-coupled receptors (GPCRs) superfamily. AT1 and AT2 receptors may have antagonistic action. While the crystal structures of GPCRs obtained from the rhodopsin, opsin, and B1 and B2- adrenergic receptors have recently been described in different conformational states, the crystal structures of Ang II receptors have not been elucidated. The conformation range and dynamics of the effects of ligands on GPCRs may differ from one receptor to another. This review focuses on the structure and function of Ang II receptors, such as the movement of transmembrane helices, functional selectivity for AT1 receptor activation, the possibility of constitutive activity of wild-type Ang II receptors and the homo- and hetero-dimerization of Ang II receptors.

The octapeptide angiotensin II (Ang II) plays a homeostatic role in the regulation of blood pressure and water and electrolyte balance, and also contributes to the progression of cardiovascular remodeling. Ang II activates Ang II type 1 (AT1) receptor and type 2 (AT2) receptor, both of which belong to the seven-transmembrane, G protein-coupled receptor family. Most of the actions of Ang II such as promotion of cellular prolifaration, hypertrophy, and fibrosis are mediated by AT1 receptor. However, in some pathological situations, AT2 receptor shows an increase in tissue expression and functions to antagonize the actions induced by AT1 receptor. Recent studies have advanced our understanding of the molecular mechanisms underlying receptor activation and signal transduction of AT1 and AT2 receptor in the cardiovascular system.

Renin-angiotensin system (RAS) plays a key role in pathogenesis of cardiovascular disease and in the responsiveness for various types of medications. A large number of genetic investigations have been carried out to examine the association between gene variants of RAS and predisposition to cardiovascular diseases, such as hypertension, coronary artery disease and stroke. Even though the major results were obtained from genetic association studies of angiotensinogen or angiotensin converting enzyme, unique findings were also elucidated from investigations concerning single nucleotide polymorphisms (SNPs) of 2 types of angioteinsin II receptor genes denoted as AGTR1 and AGTR2. Both genes have many SNPs in the coding and its flanking regions but most of the studies used A1166C polymorphism of AGTR1 and G1675A polymorphism of AGTR2. In the subjects with C1166 allele of AGTR1, several investigations reported increased risk for coronary artery disease, ischemic stroke, heart failure and end-stage renal disease but not for hypertension. Interestingly, a few papers pointed out the possibility that A1166C modulates the efficacy of RAS inhibitors. In the genetic analysis of AGTR2, G1675 allele carriers had increased risk for left ventricular hypertrophy, renal insufficiency and modulated hemodynamic response to RAS inhibitors. In this review, we summarized previous investigations concerning the genetic aspects of AGTR1 and AGTR2 to consider the clinical utility of SNPs of these receptors.

Angiotensin II (Ang II) type 1 (ATl) receptor is a member of the G protein-coupled receptor superfamily and contains 359 amino acids. AT1 receptor blockers (ARBs, e.g., eprosartan, losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, and azilsartan) have been developed and are available for clinical use, and basic and clinical studies have shown that ARBs are useful for preventing the development of cardiovascular disease. While most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups), they also show slightly different structures. Some of the benefits conferred by ARBs may not be class-specific effects, and instead may be molecule-specific effects. Their common molecular structures are thought to be responsible for their class effects, whereas their slightly different structures may be important for promoting molecule-specific effects. This review focuses on current evidence regarding the class- and molecule-specific differential effects of ARBs from basic experiments to clinical settings.

Novokinin (RPLKPW) was designed based on ovokinin (FRADHPFL), a vasorelaxing peptide derived from ovalbumin. Novokinin relaxed a mesenteric artery isolated from the spontaneously hypertensive rat (SHR) at 10-5 M, and reduced SHR blood pressure at a dose of 0.1 mg/kg (po.) emulsified in 30% egg yolk. Novokinin exhibited an affinity for the AT2 receptor (Ki = 7 x 10-6M), and its antihypertensive and vasorelaxing activities were blocked by PD123319, an AT2 receptor antagonist. The hypotensive effect of novokinin in normotensive mice was not observed in the AT2 receptor-knockout mice. Its antihypertensive and vasorelaxing activities in SHR were also blocked by CAY-10441, an antagonist of the IP receptor for prostaglandin I2 (PGI2) suggesting that these activities are mediated by the AT2 receptor, followed by the prostaglandin I2-IP receptor pathway. Novokinin suppressed food intake after icv. or po. administration in mice. The anorexigenic activity was not observed in the AT2 receptor- knockout mice, but was observed in the AT1 receptor-knockout mice. The anorexigenic activities of novokinin and angiotensin II were blocked by PD123319, and ONO-AE3-208, an antagonist of the EP4 receptor suggesting that the anorexigenic activities of the AT2 agonists are mediated by the PGE2-EP4 receptor pathway downstream of the AT2 receptor. Novokinin given icv. in mice antagonized the antinociceptive effect of morphine. The antiopiod activites of novokinin and angiotensin II were are blocked by PD123319, and by ONO-AE3-240, an antagonist of the EP3 receptor, suggesting that the antiopioid activities of AT2 agonists is mediated by the PGE2-EP3 receptor downstream of the AT2 receptor.

The biological functions of angiotensin (Ang) II are mediated by two Ang II receptors, designated type 1 receptor (AT1R) and type 2 receptor (AT2R). Most of the cardiovascular effects of Ang II are mediated by AT1R that is expressed widely in the body. The expression of AT1R is up-regulated in cardiovascular lesions, and is regulated by many endogenous bioactive substances and drugs. The AT2R is generally considered to antagonize the effects of AT1R, but its precise function remains enigmatic and controversial, particularly in humans. The expression of AT2R is low in normal adult animals, but AT2R expression is up-regulated in cardiovascular lesions. The dynamic regulation of AT1R and AT2R expression suggests an active involvement of Ang II receptors in the development of cardiovascular diseases such as atherosclerosis, heart failure, chronic kidney diseases and cerebrovascular diseases. Further clarification of gene regulatory mechanisms of Ang II receptors may identify potential targets for the development of novel therapeutics for cardiovascular diseases.

Covalent modification of sulfur-containing amino acids in proteins by reactive oxygen species (ROS) has been attracting attention as a major post-translational modification regulating intracellular signal transduction pathways. Angiotensin II (Ang II), a major physiologically active substrate in renin-angiotensin (RAS) system, plays a central role in the pathophysiology of cardiovascular systems. Many evidences show that Ang II activates several signaling pathways via an oxidative modification of proteins by Ang II-induced ROS. Ang II induced ROS production is predominantly regulated by three enzymes: NADPH oxidase, mitochondrial respiratory complex, and nitric oxide synthase (NOS), and each enzyme-generating ROS are found to activate appropriate signaling pathways via selective oxidation of specific proteins. These reactions are negatively regulated by ROS-scavenging enzymes or disulfide bridge reducing enzymes, and functional disorders of these enzymes are found to cause cardiovascular dysfunctions. Thus, the spatial and temporal regulation of oxidative modification of signaling proteins by ROS is essential to maintain cardiovascular homeostasis by Ang II. This review brings in the new aspect in understanding ROS-mediated regulation of cardiovascular homeostasis by Ang II, and provides the possible mechanisms underlying metamorphosis of cardiovascular homeostasis by ROS.

Current national guidelines have recommended the use of renin-angiotensin system inhibitors, including angiotensin II type 1 receptor blockers (ARBs), in preference to other antihypertensive agents for treating hypertensive patients with chronic kidney disease. However, the mechanisms underlying the renoprotective effects of ARBs are multiple and complex. Blood pressure reduction by systemic vasodilation with an ARB contributes to its beneficial effects in treating kidney disease. Furthermore, ARB-induced renal vasodilation results in an increase in renal blood flow, leading to improvement of renal ischemia and hypoxia. ARBs are also effective in reducing urinary albumin excretion through a reduction in intraglomerular pressure and the protection of glomerular endothelium and/or podocyte injuries. In addition to blocking angiotensin II-induced renal cell and tissue injuries, ARBs can decrease intrarenal angiotensin II levels by reducing proximal tubular angiotensinogen and production of collecting duct renin, as well as angiotensin II accumulation in the kidney. In this review, we will briefly summarize our current understanding of the pharmacological effects of an ARB in the kidney. We will also discuss the possible mechanisms responsible for the renoprotective effects of ARBs on type 2 diabetic nephropathy.

The Ang II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) is a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R signaling at local tissue sites and also in the pathophysiology of hypertension and its associated end-organ injury. Furthermore, the activation of ATRAP in transgenic-models inhibited inflammatory vascular remodeling and cardiac hypertrophy in response to Ang II stimulation. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and related organ injury.

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, and also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Blockade of renin-angiotensin system (RAS) attenuates weight gain and adiposity by enhanced energy expenditure, and 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. Similarly, bone metabolism is closely regulated by hormones and cytokines, which have effects on both bone resorption and deposition. It is known that the receptors of Ang II are expressed in culture osteoclasts and osteoblasts, and Ang II is postulated to be able to act upon the cells involved in bone metabolism. In in vitro system, Ang II induced the differentiation and activation of osteoclasts responsible for bone resorption. Importantly, it was demonstrated by the sub-analysis of a recent clinical study that the fracture risk was significantly reduced by the usage of angiotensinconverting enzyme inhibitors. To treat the subgroups of hypertensive patients with osteoporosis RAS can be considered a novel target.

For the past century, the renin–angiotensin system (RAS) has been recognized as one of the major blood pressure-regulating systems. Angiotensin II (Ang II) is the final physiologically active product of RAS, and it works not only as a strong vasopressor but also as a promotor of tissue remodeling in various organs such as heart, arteries, and kidneys. RAS is the predominant pathway of Ang II formation in human plasma, but not in the tissues. There are several alternative pathways producing angiotensin II in human tissues, and they are involved in structural remodeling of the cardiovascular system. Proteinases such as chymase, kallikrein, cathepsin G, and elastase- 2 are probably responsible for angiotensin-converting enzyme (ACE)-independent Ang II formation in human tissues. In particular, chymase is an important Ang II-generating enzyme in the human heart. It is important to elucidate the mechanisms of the ACEindependent Ang II formation in human tissues; long-term inhibition of the local Ang II formation may become one of the strategies to prevent cardiovascular remodeling.

In the classical renin angiotensin system (RAS), angiotensin II (Ang II) plays many important roles in cardiovascular disease and in kidney, brain, and other organs via the Ang II type 1 receptor (AT⊂ 1). The RAS consists of many angiotensin peptides, including Ang (1-7), Ang (1-9), Ang (2-8), and Ang IV. Ang (1-7), produced by angiotensin-converting enzyme 2 (ACE2), has received attention because ACE2-deficient mice have heart failure. In addition, the proto-oncogene mas and insulin regulatory aminopeptidase (IRAP) have been identified as receptors for Ang (1-7) and Ang IV, respectively, accelerating investigations into both peptides. Many groups have suggested that the ACE2/Ang (1-7)/mas axis results in beneficial effects in cardiovascular disease, renal damage, and glucose intolerance and plays an independent role in kidney disease and glucose metabolism. On the other hand, Ang IV/IRAP strongly influences memory disturbance and protects against brain ischemia. Finally, the classical RAS-ACE/Ang II/AT1 axis blockade yields beneficial effects in the context of organ damage, and additional modulation of ACE2/Ang (1-7)/mas or angiotensin IV/IRAP with this blockade results in even greater improvement. In the near future, new treatments targeting RAS and using new angiotensin peptide players might be developed for managing lifestyle-related diseases.

Chymase, a chymotrypsin-like serine protease that is abundant in secretory granules from mast cells, has been identified to be a key enzyme in the local renin-angiotensin system (RAS) that generates angiotensin II (Ang II) independent of angiotensin converting enzyme (ACE). The pathophysiological significance of alternative Ang II-forming pathways in human cardiovascular disease remains controversial. Although chymase inhibitors, unlike ACE inhibitors and Ang II type 1 receptor blockers (ARBs), may only play a small role in the regulation of the systemic RAS, the possible applications of chymase inhibitors as new drugs that inhibit the local RAS to prevent cardiovascular diseases are described in animal models. In this review, we discuss the possible application of chymase inhibitors as new drugs to inhibit the RAS in mainly cardiovascular diseases.

The inverse association of cardiovascular risk with intake of omega-3 polyunsaturated fatty acids was suspected early in populations that are known to have a high consumption of fish and fish oil. Subsequent cohort studies confirmed such associations in other populations. Further evidence of possible beneficial effects on metabolism and cardiovascular health was provided by many studies that were able to show specific mechanisms that may underlie these observations. These include improvement of the function of tissues involved in the alterations occurring during the development of obesity and the metabolic syndrome, as adipose tissue, the liver and skeletal muscle. Direct action on the cardiovascular system was not only shown regarding vascular function and the formation of atherosclerotic plaques, but also by providing antiarrhythmic effects on the heart. Data on these effects come from in vitro as well as in vivo studies that were conducted in animal models of disease, in healthy humans and in humans suffering from cardiovascular disease. To define prophylactic as well as treatment options in primary and secondary prevention, large clinical trial assessed the effect of omega-3 polyunsaturated fatty acids on end points as cardiovascular morbidity and mortality. However, so far these trials provided ambiguous data that do allow recommendations regarding the use of omega-3 polyunsaturated fatty acids in higher dosages and beyond the dietary advice of regular fish intake only in few clinical situations, such as severe hypertriglyceridemia.

The clinically most relevant medications for lipid management are the statins, which constitute in the majority of the cases the basis of any lipid-modulating therapy. However, other agents are often needed to either reduce low-density cholesterol to target levels and/or to treat residual serum lipoprotein abnormalities. Niacin is currently the most potent available agent to increase high-density lipoprotein and reduce lipoprotein(a), both independent risk factors for cardiovascular disease. Niacin also has been found to reduce inflammatory markers like C-reactive protein (CRP) and lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to decrease small-dense LDL and increase large-particle LDL, all potentially anti-atherosclerotic properties. Through its action on the GPR109A receptor niacin seems to also exert various pleiotropic effects such as improvement of endothelial function and reduction of inflammation and oxidative stress. However, niacin is often underused in the clinical setting, mainly due to either potentially preventable or disproportionally feared side effects such as flushing, hyperglycemia, and hyperuricemia, respectively. Even though the results of the AIM-HIGH trial were negative, the results of the larger end point trial HPS2-THRIVE are still pending. Based on the totality of existing evidence, niacin should in the mean time remain high in the list of lipid-modulating agents to be used in clinical practice, second after statins.

Ezetimibe, an inhibitor of intestinal cholesterol absorption, can decrease total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B levels and increase high-density lipoprotein cholesterol (HDL-C) levels. Apart from lipid-lowering, ezetimibe may exert certain off-target actions (e.g. anti-inflammatory, anti-atherogenic and antioxidant) thus contributing to a further decrease of cardiovascular disease (CVD) risk. Ezetimibe trials resulted in controversial outcomes with some studies reporting atherosclerosis regression and reductions in CVD events following ezetimibe therapy in combination with a statin while others reported negative results. The results of the ongoing IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) which compares ezetimibe plus simvastatin with simvastatin monotherapy with regard to CVD outcomes after acute coronary syndromes should further elucidate the effect of ezetimibe on CVD events. This review presents the results of up-to-date clinical trials with ezetimibe and summarizes its potential pleiotropic effects. Furthermore, we comment on the administration of ezetimibe in treating high-risk patients [i.e. with diabetes mellitus (DM), metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), peripheral artery disease (PAD) or carotid disease]. The use of ezetimibe either as monotherapy or as add-on therapy in daily clinical practice is also discussed.

Treatment with statins represents an essential component both of primary and secondary cardiovascular prevention strategies. However, a proportion of patients cannot reach low-density lipoprotein cholesterol (LDL-C) targets with the highest tolerable dose of a potent statin or is intolerant to statins. Several treatment options are available for these patients. Colesevelam is a relatively new bile acid sequestrant that decreases serum LDL-C levels. Moreover, colesevelam improves glycemic control and seems to be well-tolerated, at least in short-term studies. Therefore, colesevelam seems to be a useful tool for the management of high-risk patients who cannot achieve LDL-C targets with monotherapy with a potent statin.

Dyslipidemia, and especially atherogenic dyslipidemia, a combination of small low-density lipoproteins cholesterol (LDL-C), decreased high-density lipoprotein cholesterol (HDL-C) and increased triglyceride (TG) concentrations, represents a major cardiovascular (CV) risk factor. Nuclear receptor peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid metabolism; PPAR ligands are used to treat dyslipidemias. Fibrates have a major impact on TG metabolism as well as on modulating LDL size and subclasses. Fibrates target atherogenic dyslipidemia by increasing plasma HDL-C concentrations and decreasing small dense LDL (sdLDL) particles and TGs, thus contributing to dyslipidemia management, particularly in patients with diabetes (DM) or the metabolic syndrome (MetS). Furthermore, fibrates exert beneficial effects on adipokines, inflammation and oxidative stress as well as neuroprotective properties. However, further studies are needed to define the role of fibrates in the prevention of CV events. We review the effects of fibrates on atherogenic dyslipidemia and CV risk reduction.