Overview of the Renin-Angiotensin System

Angiotensin II is an octapeptide hormone of the renin-angiotensin system (RAS), and it regulates a wide variety of physiological responses including salt and water balance, the blood pressure and the vascular tone. Clinical trials with angiotensin-converting enzyme (ACE) inhibitors have demonstrated survival benefits in subjects with congestive heart failure and myocardial infarction, and this support the importance of angiotensin II in the pathogenesis of cardiovascular diseases. Through activation of small G proteins such as Ras, Rho, and Rac, angiotensin II induces remodeling of vascular smooth muscle cells (VSMC), including proliferation, migration, hypertrophy and inflammation. Angiotensin (1-7) appears to be the main effector peptide of ACE2 with vasodilatory, natriuretic and antiinflammatory properties. The cross-talk between the angiotensin II receptors may play an important role in maintaining cardiovascular homeostasis.

Related papers:

title: Role of the renin–angiotensin–aldosterone system in vascular remodeling and inflammation: a clinical review
abstract: The concept of hypertension as primarily a consequence of altered hemodynamics has changed. Many factors are now implicated in the development of hypertensive vascular disease, and the renin–angiotensin–aldosterone system (RAAS) appears to be one of the most significant. Angiotensin II, the principal effector peptide of the RAAS, has far-reaching effects on vascular structure, growth and fibrosis, and is a key regulator of vascular remodeling and inflammation. Reactive oxygen species and a network of signaling pathways mediate angiotensin II and cellular mechanisms that promote remodeling and inflammation. The involvement of aldosterone in vessel-wall and myocardial remodeling has also come under intensive research scrutiny. Treatments that block the pathologic effects of the RAAS at several points have been shown to limit target-organ damage in hypertension and to decrease cardiovascular morbidity and mortality. Understanding the molecular and cellular mechanisms that participate in the early development of hypertensive vascular disease may lead to more targeted treatment and improved outcomes.

title: Angiotensin II signal transduction through small GTP-binding proteins: mechanism and significance in vascular smooth muscle cells.
abstract: Small GTP-binding proteins (G proteins) are monomeric G proteins with a low molecular weight of 20 to 40 kDa. A small G protein acts as a molecular switch that cycles between inactive GDP-bound and active GTP-bound forms. Thus far, >100 small G proteins have been identified in eukaryotes from yeast to humans. The small G proteins in this superfamily are structurally classified into ≥5 families: the Ras, Rho, Rab, Sar/Arf, and Ran families. In general, the Ras family mainly regulates gene expression, the Rho family regulates both cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate intracellular vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization during the cell 

Multiple downstream effectors of small G proteins, some of them being protein kinases, have been identified. Ras mediates its effect on cell proliferation mainly by activation of its effector Raf to initiate the mitogen-activated protein kinase (MAPK/extracellular signal regulated kinase [ERK]) cascade. In addition, a variety of Ras effectors have been identified, such as a phosphatidylinositol 3-kinase (PI3K). The Rho family, such as Rho, Rac, and Cdc42, also has various effectors. One of the Rho effectors, Rho-kinase (ROCK), plays an important role in actin cytoskeleton reorganization and smooth muscle contraction. In addition, reduced nicotinamide-adenine dinucleotide phosphate oxidase is known as a Rac effector and p70 S6 kinase (p70S6K) as a Cdc42 effector.1,2 Recently, small G proteins have been noted as novel therapeutic targets in cardiovascular medicine. In this regard, Ras and Rho G proteins are the most investigated molecules in the cardiovascular system. It has been shown that Ras is involved in growth of cultured vascular smooth muscle cells (VSMCs).3 Also, various vasoactive factors stimulate RhoA and ROCK, leading to enhanced vasoconstriction and migration of VSMCs.4

Angiotensin II (Ang II), the …

title: The cardiovascular continuum and renin–angiotensin–aldosterone system blockade
abstract: A progressive chain of pathophysiological events links cardiovascular risk factors to clinical manifestations of disease and life-threatening cardiovascular events. This chain – the cardiovascular continuum – underlies cardiovascular disease and holds the key to its prevention and treatment. Progressive tissue damage can result in morbidity from congestive heart failure, end-stage heart disease, nephrotic proteinuria and dementia and, eventually, death from cardio- or cerebrovascular causes. The renin–angiotensin–aldosterone system (RAAS) is involved at all stages of the cardiovascular continuum, because the effector molecules of the RAAS, angiotensin II in particular, have direct pathobiological effects on a variety of tissues, including the endothelium, vascular smooth muscle and the renal mesangium. Clinical trials of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors have demonstrated the essential validity of this hypothesis. Interruption of the RAAS has been shown to reduce cardiovascular morbidity and mortality in patients with left ventricular hypertrophy, heart failure and post-myocardial infarction, as well as renal disease in patients with type 2 diabetes. Key questions remain, however. What are the clinical effects of combination ARB and ACE inhibitor treatment? How will combinations of RAAS blockade with other agents, such as statins, affect the cardiovascular continuum? Answers to these questions will require well-planned, adequately powered clinical trials, such as the Programme of Research tO evaluate Telmisartan End-organ proteCTION (PROTECTION) and the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) programmes. However, it is already clear that RAAS blockade is an essential part of blocking progression along the cardiovascular continuum.

title: Blockade of the renin–angiotensin–aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes
abstract: Diabetes (particularly type 2 diabetes) represents a global health problem of epidemic proportions. Individuals with diabetes are not only more likely to develop hypertension, dyslipidemia, and obesity, but are also at a significantly higher risk for coronary heart disease, peripheral vascular disease, and stroke. Angiotensin II plays a key pathophysiological role in the progression of diabetic renal disease, and blockade of the renin–angiotensin system with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II antagonists has therefore become an important therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. Several studies have demonstrated the effects of angiotensin II antagonists on the reduction of albuminuria and the progression of renal disease from microalbuminuria to macroalbuminuria. More importantly, several endpoint trials have shown that the antiproteinuric effects of losartan and irbesartan translate into cardiovascular and renoprotective benefits beyond blood pressure lowering, thereby delaying the need for dialysis or kidney transplantation by several years. These and other studies indicate that angiotensin II antagonists not only improve survival and quality of life of patients with diabetic nephropathy, but also have the potential to reduce the substantial healthcare burden associated with managing these patients. ACEi also appear to exert similar beneficial effects in diabetic patients, but whether clinically significant differences in renoprotection or mortality exist between angiotensin II antagonists and ACEi in patients with type 2 diabetes remains to be fully investigated in appropriate head-to-head studies.

title: Hypertension treatment and implications of recent cardiovascular outcome trials
abstract: Clinical trials have shown that effective control of blood pressure reduces the risk of cardiovascular events in high-risk patients. For example, data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study show significant reductions in the incidence of cardiac events, stroke and all-cause mortality in patients in whom blood pressure control was achieved compared with those in whom blood pressure remained uncontrolled. Although the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) demonstrated no significant difference in cardiovascular mortality and morbidity between patients receiving diuretics, calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors, this finding might have been confounded by differences in the blood pressure reductions achieved with the three treatments. Other studies have consistently shown that newer antihypertensive agents, such as ACE inhibitors and calcium channel blockers, reduce cardiovascular events to a similar, or possibly greater, extent as older therapies, such as diuretics and β-blockers. In particular, ACE inhibitors appear to offer additional benefits beyond blood pressure reduction in terms of reducing cardiovascular events and producing renoprotective effects. Angiotensin II receptor blockers (ARBs) have been less extensively studied, but there is evidence already that they have heart failure, stroke and renoprotective benefits. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is currently comparing the effects of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg, alone and in combination, on cardiovascular events in high-risk patients.

title: Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke
abstract: Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.

title: New evidence on the importance of the renin–angiotensin system in the treatment of higher-risk patients with hypertension
abstract: We reviewed the drug treatment of hypertension in the light of recent trials. β-Blockers and diuretics clearly reduce mortality, strokes, and coronary heart disease (CHD) in hypertension. Recent trials assessed whether newer agents that block the renin–angiotensin–aldosterone system, or calcium blockers, offer any additional advantage, or have benefits in high-risk individuals with conventionally ‘normal’ blood pressure. The recent ALLHAT study claimed no differences in CHD or mortality when chlorthalidone, amlodipine, and lisinopril were compared. However, the decrease in blood pressure was not the same with the three agents, and a substantial proportion of patients enrolled did not have clinical disease. In contrast, the LIFE study (comparing losartan and a β-blocker) and the ANBP-2 study [comparing angiotensin-converting enzyme (ACE) inhibition and a diuretic] reduced blood pressure similarly, yet demonstrated benefits in favour of angiotensin II type 1 receptor blockers (ARBs) and ACE inhibitors. Other trials indicated similar advantages of ACE inhibitors or ARBs in patients with diabetic nephropathy. Among high-risk patients with initial blood pressure in the ‘normal’ range, ACE inhibitors significantly reduce clinical events (mortality, strokes, and myocardial infarction), despite modest decreases in blood pressure, suggesting that additional mechanisms are responsible. Recent results of the Prospective Studies Collaboration show lower risk, even in the normal blood pressure range; high-risk patients will benefit further from ACE inhibitors and ARBs (and β-blockers after myocardial infarction). Data for other blood pressure decreasing agents are unavailable in such populations. We conclude that blood pressure decreasing per se is of clinical benefit, but drugs that block the renin–angiotensin system offer additional advantages. Drug choice is best determined by the patient's clinical condition.

title: Role of Angiotensin II Receptor Blockers in the Treatment of Congestive Heart Failure
abstract: Pharmacotherapy for the treatment of heart failure has advanced considerably in recent years, and clinical trials have demonstrated the favorable long-term effects of angiotensin-converting enzyme inhibitors (ACEI and beta- blockers on the morbidity and mortality. Although the current guidelines recommend ACEI and beta-blockers as standard therapy for heart failure, as they have demonstrated benefits in terms of mortality, only one third of patients with heart failure are receiving both classes of drug due to concern over their adverse effects. The benefit of ACEI has been attributed largely to blockade of angiotensin II production, but also to the accumulation of bradykinin. The accumulation of bradykinin however, has been implicated as contributing to adverse effects, such as a dry cough, associated with ACEI treatment, and has also been suggested to result in prejunctional norepinephine release. Recently, many clinical trials have shown that angiotensin receptor blockers (ARBs had similar effect on the mortality and morbidity of patients with heart failure. The side effects, notably the cough, are significantly less than with ACE inhibitors. ARBs could also be recommended for patients who can not tolerate ACE inhibitors for symptomatic treatment. In combination with ACEI, ARBs may improve the sym- ptoms of heart failure, and reduce hospitalizations due to heart failure deterioration. Whether concomitant beta- blockade negatively affects the effect of ARB will require further evaluation. In this paper, recent large clinical trials of ARBs therapy in heart failure, and the ongoing clinical trials, were reviewed for the recommendation of the optimal conditions for ARBs treatment in heart failures. (Korean Circulation J 2002;32(12 :1039-1045

title: Total cardiovascular risk: a new treatment concept
abstract: Recognition that cardiovascular risk factors, such as hypertension, dyslipidaemia and diabetes mellitus, often cluster together has focused attention on the concept of total cardiovascular risk. Most current hypertension management guidelines emphasize the importance of assessing and managing the total risk in an individual patient. Due to the presence of additional risk factors, target-organ damage and associated clinical conditions, patients may be at high risk of cardiovascular events even when their blood pressure is normal or high-normal (systolic blood pressure 130–139 mmHg, diastolic blood pressure 80–89 mmHg). Such high-risk patients, although common in clinical practice, are often under-diagnosed. Intensive hypertensive therapy is recommended for high-risk patients. In most cases, this will necessitate combination therapy with two or more drugs. Moreover, antihypertensive therapy should form one component of a multifactorial approach aimed at treating all reversible risk factors. In the future, research should be aimed at controlling or reversing subclinical target-organ damage, the ultimate aim being to prevent the progression of cardiovascular risk in individuals at low or medium risk.

title: Angiotensin II signal transduction and the mitogen-activated protein kinase pathway.
abstract: In this review, the angiotensin-II-mediated signal transduction pathways involved in vascular smooth muscle cell growth are discussed. Classical pathways involving phospholipase C and protein kinase C, as well as the mitogen-activated protein kinase pathway, are common signal transduction pathways activated by a variety of growth factors to stimulate cell growth. Besides its vasoconstrictor activity, angiotensin II stimulates hypertrophy of vascular smooth muscle cells and is involved in neointimal proliferation following balloon angioplasty. Understanding angiotensin-II-stimulated signaling events, as well as the crosstalk among signaling pathways, may form the basis for the development of new therapies for hypertension and restenosis.

title: The renin-angiotensin system and vascular hypertrophy.
abstract: In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.

title: Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases.
abstract: In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.

title: How do angiotensin II receptor antagonists affect blood pressure?
abstract: The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. Angiotensin II is the principal effector hormone in the RAS, causing vasoconstriction and increased sodium and water retention, leading to increased blood pressure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists both inhibit the actions of angiotensin II. ACE inhibitors prevent the formation of angiotensin II from angiotensin I, whereas angiotensin II receptor antagonists inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. This article discusses the efficacy of angiotensin II receptor antagonists and their possible role in organ protection.

title: Aldosterone and Angiotensin II Synergistically Induce Mitogenic Response in Vascular Smooth Muscle Cells
abstract: Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10−12 mol/L) and with a lower dose of Ang II (10−10 mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.

title: Nox1 Overexpression Potentiates Angiotensin II-Induced Hypertension and Vascular Smooth Muscle Hypertrophy in Transgenic Mice
abstract: Reactive oxygen species (ROS) have been implicated in the development of cardiovascular pathologies. NAD(P)H oxidases (Noxes) are major sources of reactive oxygen species in the vessel wall, but the importance of individual Nox homologues in specific layers of the vascular wall is unclear. Nox1 upregulation has been implicated in cardiovascular pathologies such as hypertension and restenosis.  To investigate the pathological role of Nox1 upregulation in vascular smooth muscle, transgenic mice overexpressing Nox1 in smooth muscle cells (TgSMCnox1) were created, and the impact of Nox1 upregulation on the medial hypertrophic response during angiotensin II (Ang II)–induced hypertension was studied. These mice have increased expression of Nox1 protein in the vasculature, which is accompanied by increased superoxide production. Infusion of Ang II (0.7 mg/kg per day) into these mice for 2 weeks led to a potentiation of superoxide production compared with similarly treated negative littermate controls. Systolic blood pressure and aortic hypertrophy were also markedly greater in TgSMCnox1 mice than in their littermate controls. To confirm that this potentiation of vascular hypertrophy and hypertension was due to increased ROS formation, additional groups of mice were coinfused with the antioxidant Tempol. Tempol decreased the level of Ang II-induced aortic superoxide production and partially reversed the hypertrophic and hypertensive responses in these animals.  These data indicate that smooth muscle-specific Nox1 overexpression augments the oxidative, pressor, and hypertrophic responses to Ang II, supporting the concept that medial Nox1 participates in the development of cardiovascular pathologies.

title: AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions.
abstract: In various manifestations of cardiovascular disease, blockade of the renin–angiotensin system by angiotensin converting enzyme (ACE) inhibitors has been shown to prevent or delay disease progression effectively and improve prognosis in terms of mortality and morbidity. Angiotensin type 1-receptor (AT1-receptor) blockers, on the other hand, are used for more specific and efficacious blockade of the renin–angiotensin system, by blocking the deleterious effects of the activated renin–angiotensin system selectively and effectively at the receptor level. The introduction of this pharmacological principle is in line with the general development of more refined drug interaction with biological systems. Several AT1receptor blockers are available, and those currently accessible for clinical use are listed in Table 1. Pharmacological differences exist between AT1receptor blockers (Table 2), but no definite data indicate that these differences have clinical relevance. Indeed, according to the American Food and Drug Administration, there are no differences between AT1-receptor blockers in terms of blood pressure lowering. However, recent results from studies in patients with heart failure using different AT1-receptor blockers are conflicting, raising the question of whether clinically relevant differences might exist. Losartan, first registered in Sweden in September 1994 for use in hypertension, is the first and, so far, the most extensively documented substance in this group. In many countries, several AT1-receptor blockers have since become available for clinical use, including for the treatment of heart failure (Table 1). Clinical experience in general practice is extensive and AT1-receptor blockers have been prescribed to several million patients

title: Angiotensin II receptor blockade and end-organ protection: pharmacological rationale and evidence.
abstract: The renin-angiotensin system is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is the production of the active peptide angiotensin II. Because angiotensin II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the renin-angiotensin system. Angiotensin II also may be involved in end-organ damage in hypertension, heart failure, and vascular disease.


ANGIOTENSIN II RECEPTORS
At least two subtypes of angiotensin II receptors have been identified, angiotensin type 1 (AT)1 and type 2 (AT2). The AT1 receptor mediates all the known actions of angiotensin II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known about the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses the AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects.



This newly introduced class of drugs is able to inhibit the renin-angiotensin system at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of angiotensin II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1 receptor antagonists may provide end-organ protection by blocking angiotensin II effects via the AT1 receptor, leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction and other conditions resulting from structural alterations in the heart, kidney, and vasculature.

title: Angiotensin II and Cell Cycle Regulation
abstract: Angiotensin II has emerged as an important growth factor for vascular, cardiac, and renal cells. Depending on the specific cell type and presence of other growth factors, angiotensin II induces proliferation (replication of DNA with subsequent successful division of cells), hypertrophy (increase in cell size, cell protein, and mRNA content without DNA replication), apoptosis (programmed cell death), or differentiation. Such angiotensin II-mediated modulation of growth process may underlie various pathophysiological processes such as atherosclerosis, vascular and cardiac remodeling, and progression of chronic renal disease. Clearly, angiotensin II-induced proliferation requires complete cell progression through the various steps of the cell cycle. In contrast, cells undergoing angiotensin II-mediated hypertrophy are arrested in the G1-phase. Upregulation of cell cycle-dependent kinase inhibitors (eg, p27Kip1) plays an important role in this process. Although accumulating evidence suggests that apoptosis is cell cycle-dependent, only few data are currently available concerning the interaction of angiotensin II with the cell cycle machinery in apoptosis. We review the various angiotensin II-mediated growth processes and their relationship to events governing cell cycle regulation.

title: Role of Angiotensin II Type 1A Receptor-Mediated Signaling in the Development of Pressure Overload-Induced Left Ventricular Hypertrophy and Fibrosis
abstract: Objectives：The roles of angiotensin II (Ang II) in the regulation of heart function under normal and pathological conditions have been well documented, with its biological actions mainly mediated via the Ang II type 1A receptor (AT1AR). Since the inhibition of the renin-angiotensin system can prevent or regress left ventricular hypertrophy (LVH) with hypertension, AT1AR-mediated signaling is considered one of the important transcriptional pathways in the development of cardiac hypertrophy. Subjects and Methods：To address whether AT1AR-mediated signaling plays an important role in the development of pressure overloadinduced LVH and fibrosis, the physiological, biochemical, hemodynamic and histopathological parameters were evaluated before and after transverse aortic constriction (TAC) in wild-type (WT) and AT1AR knockout (KO) mice. Results：Although the LV systolic pressure (83.2±10.0 mmHg, n=5) of the KO mice was lower than that (90.0±5.0 mmHg, n=7) of the WT mice, there was no difference in the increase in the LV systolic pressure between the WT and KO mice (WT, 42.0 mmHg; KO, 41.8 mmHg). Also, there was no difference between the baseline LV-to-body weight (LVW/BW) ratio between the two groups (WT, 3.10±0.21 mg/g; KO 3.04±0.21 mg/g). Two weeks after TAC, the degree of increase in the LVW/BW ratio was markedly increased in both the WT (4.17±0.28 mg/g, n=9) and KO mice (4.16±0.43 mg/g, n=8), which were almost identical (WT, 34.5%; KO, 36.8%). There were no significant differences in the LV end-diastolic pressure, LV+dP/dtmax, and heart rate between the two groups. The ERK44/42 and p38-MAPK activities in the LV were markedly increased by TAC in both groups, but that of JNK was not. Interstitial and perivascular fibrosis developed in both groups following TAC. However, the degree of increased fibrosis was significantly attenuated in the KO mice. Conclusion：These results suggest AT1AR-mediated signaling is not indispensable for the development of pressure overload-induced LVH, and provides new insights into the development of novel therapeutic strategies for cardiac hypertrophy. (Korean Circulation J 2006;36:626-634)

title: The prothrombotic paradox of hypertension: role of the renin-angiotensin and kallikrein-kinin systems.
abstract: Despite increased pulsatile stress, thrombotic rather than hemorrhagic events represent a major complication of hypertension. The pathophysiology of thrombosis in hypertension involves the interaction among vascular endothelium and particularly the renin-angiotensin and kallikrein-kinin systems. Because hypertension is often associated with some degree of inflammation, the combination of chronic inflammation and chronic shear stress may convert the normal anticoagulant endothelium into a procoagulant surface, expressing tissue factor. Activation of the renin-angiotensin system leads to activation of nuclear factor kappaB-dependent proinflammatory genes, also accelerating the expression of tissue factor. Renin-angiotensin and kallikrein-kinin systems interact at several levels to modulate coagulation, fibrinolysis, and vasodilatation in such a way that these 2 systems could have a major influence on the occurrence of thrombotic complications. Treatment with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists may favorably influence the balance between the renin-angiotensin and kallikrein-kinin axis, regulating blood pressure as well as reducing the risk of thrombosis, which may explain part of the clinical efficacy of these drugs.

title: Angiotensin-converting enzyme inhibitors.
abstract: ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.

title: Signaling by the Angiotensin-Converting Enzyme
abstract: Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Because of its dual role in regulating angiotensin II and bradykinin levels, the positive clinical effects of ACE inhibitors were thought to be the consequence of concomitant reductions in the production of angiotensin II and the degradation of bradykinin. Recent evidence suggests that some of the beneficial effects of ACE inhibitors on cardiovascular function and homeostasis can be attributed to novel mechanisms. These include the accumulation of the ACE substrate N-acetyl-seryl-aspartyl-lysyl-proline, which blocks collagen deposition in the injured heart, as well as the activation of an ACE signaling cascade that involves the activation of the kinase CK2 and the c-Jun N-terminal kinase in endothelial cells and leads to changes in gene expression. Moreover, at least one other ACE homologue (ACE2) is proposed to counteract the detrimental effects associated with the activation of the classical renin-angiotensin system. These data reveal hitherto unexpected levels of internal regulation of the renin-angiotensin system.

title: The importance of left ventricular hypertrophy in human hypertension.
abstract: Hemodynamic and non-hemodynamic factors contribute to the development of left ventricular hypertrophy (LVH). The presence of LVH is an important independent risk factor for total mortality and for cardiovascular morbidity and mortality. Direct cardiac effects of LVH include an increased risk of developing of congestive heart failure, an increased risk of arrhythmic events, and a reduced coronary flow reserve, promoting myocardial ischemic episodes. In addition, hypertension may promote the development of coronary artery atherosclerosis. The prognostic implications of LVH underscore the importance of diagnostic procedures. The electrocardiogram has a high specificity to identify patients with LVH but the sensitivity is fairly low. Echocardiography provides higher sensitivity and also gives important information, such as the pattern of left ventricular geometry, which is of prognostic importance, and the presence of diastolic dysfunction, which is an early abnormality in the evolution of hypertensive LVH. Reversal of LVH appears to improve prognosis. Reduction of blood pressure is one important component in the regression of LVH. Important quantitative differences exist between drug classes in the reversal of cardiac hypertrophy despite similar antihypertensive effects, suggesting other factors to be of importance in the regression of left ventricular mass. LVH is reduced more by angiotensin-converting enzyme inhibitors than by other antihypertensive drug classes, suggesting an effect on structural myocardial changes beyond that provided by the reduction of blood pressure. Recent data suggest that angiotensin II receptor antagonists (AIIRAs) have quantitatively similar effects on left ventricular mass as do angiotensin-converting enzyme inhibitors. A comparative trial of the AIIRA irbesartan and the beta-blocker atenolol demonstrated that despite similar reductions in blood pressure, the reductions attained in left ventricular mass with irbesartan were progressive and numerically greater than those attained with atenolol. Taken together, these findings provide circumstantial evidence for an important role of angiotensin II acting on angiotensin type 1 (AT1) receptors in the development or maintenance of cardiac hypertrophy. Confirmation of the favorable effects of angiotensin-converting enzyme inhibitors and AIIRAs on left ventricular mass in larger trials, including those assessing cardiovascular morbidity and mortality, will be of major importance in the future treatment of hypertension.

title: Left ventricular hypertrophy as a predictor of cardiovascular risk
abstract: Left ventricular hypertrophy (LVH) is a potent, independent predictor of cardiovascular events, particularly in hypertension, in which it dramatically increases the risk of stroke, coronary heart disease and heart failure. LVH is predominantly a surrogate marker for the effects of other risk factors integrated over time, but it may also contribute directly to cardiovascular disease through pathological changes in cardiac structure. The influence of blood pressure is central to LVH pathology, with 24-h blood pressure being more predictive of LVH than single clinic measurements. Blood pressure variation throughout the day is also emerging as an important correlate of LVH, and a strong association has been found between the early morning blood pressure rise and increased left ventricular mass. Antihypertensive treatment can reverse LVH, and preliminary studies suggest that this improves cardiovascular outcome and long-term prognosis. Most classes of antihypertensive agent show some effect on LVH regression, with the notable exceptions of minoxidil and hydralazine. However, many of the data regarding LVH regression come from small, poor-quality trials or from meta-analyses of these studies. In the few well-conducted studies that are available, certain classes of antihypertensive drugs are more effective than others. Those that target angiotensin II, such as the angiotensin II receptor blockers, appear to have a specific action on LVH that is independent of blood pressure reduction. Further high-quality studies are needed to define how LVH predicts cardiovascular risk, which agents are most effective at eliciting LVH regression and how such reversal can affect cardiovascular outcome.

title: An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.
abstract: A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.

title: Vascular hypertrophy in hypertension: role of the renin-angiotensin system.
abstract: Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.

title: Effects of antihypertensive drugs on vascular remodeling: do they predict outcome in response to antihypertensive therapy?
abstract: Remodeling of large and small arteries in hypertension contributes to elevation of blood pressure, and may participate in the complications of hypertension. Large arteries exhibit increased lumen size, thickened media with increased collagen deposition, and decreased compliance, which contributes to raised systolic blood pressure and pulse pressure. In small (resistance) arteries smooth muscle cells are restructured around a smaller lumen, without true hypertrophy, particularly in milder forms of hypertension, whereas in severe forms and in secondary hypertension hypertrophic remodeling has been reported. Endothelial dysfunction occurs in many patients, with prevalence similar to that of left ventricular hypertrophy. Treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor subtype 1 antagonists and long-acting calcium channel blockers has corrected changes in large and small arteries in hypertensive patients. Treatment with β-blockers did not modify either structure or function of small arteries. Improved outcomes were reported in clinical trials with drugs that exert vascular protective effects, such as angiotensin-converting enzyme inhibitors and angiotensin receptor subtype 1 antagonists, as well as with those that do not appear to improve vascular structure or function. Recent trials suggest that these different drugs may provide similar benefits essentially through blood pressure lowering, although some minor differences between drugs have been noted. For example, the α-blocker doxasozin has been associated with worse outcomes (heart failure) than have diuretics. That hard end-point clinical trials have not demonstrated any advantages of agents with vasculoprotective properties may relate in part to the relatively short duration of some of these multicenter trials (3-5 years). Another contributing factor may be the low number of events with each drug class in the longer trials. Thus, current evidence does not support the rational expectation that vasculoprotective antihypertensive agents will be associated with better outcomes in hypertensive patients, possibly because of limitations of these trials.

title: Novel therapies blocking the renin–angiotensin–aldosterone system in the management of hypertension and related disorders
abstract: Although significant advances have been made in the therapeutic blockade of the renin–angiotensin–aldosterone system (RAAS) using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and non-selective aldosterone receptor antagonists, there is a clear need for both additional blocking strategies and enhancements of current therapeutic approaches. Vasopeptidase inhibition may still find a role despite the small incremental value of this approach and the obvious issue of kinin-mediated adverse effects still to be fully addressed. Blockade of the RAAS upstream using renin inhibitors as well as the greater selectivity of aldosterone blockade using selective aldosterone blockers such as eplerenone are also novel approaches. Not yet in clinical use but certainly an attractive therapeutic target is angiotensin II growth factor receptor transactivation, with selective inhibitors having been developed for various specific kinase pathways. Finally, ACE2 augmentation, antisense gene strategies, and vaccination against the renin–angiotensin system should still be considered experimental, but have significant appeal as additional approaches to the blockade of this system.