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October 30, ; Accepted Date: December 12, ; Published Date: J Hypertens Los Angel 4: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Visit for more related articles at Journal of Hypertension: Hypertension is a major risk factor of cardiovascular diseases CVDs , and a most important health problem in developed countries.
The rennin-angiotensin-aldosterone system RAAS plays a pivotal role in controlling blood pressure or hydro-electrolyte balance. In this review we will summarize the recent findings about these new components of RAAS mainly from the viewpoint of molecular mechanism and oxidative stress. Hypertension is a common but one of the most important health problems, because it is a major risk factor for many CVDs.
So it is very important to prevent, diagnose early and treat hypertension and its complications. Renin-angiotensin- aldosterone system RAAS has been reported to be associated with hypertension and target organ damage for a long time [ 1 ]. RAAS, not only in the systemic circulation but also in the local organs and tissues, has also been shown to play a crucial role in the pathogenesis of hypertension and CVDs [ 2 - 4 ].
But the reports on the alteration in oxidative stress level brought by these new components of RAAS are rare. In this review, outlines of the these new components of RAAS and recent findings on their effect on oxidative stress will be discussed. Renin-angiotensin-aldosterone system with new components Figure 1 and oxidative stress. Outline of rennin-angiotensin-aldosterone system with new components. Mas-related G-protein coupled receptor D. Ang- receptor Mas. Black rectangles are protective receptors.
Oxidative stress has been shown to be involved in the pathogenesis of human essential hypertension, because hydrogen peroxide or superoxide anion are reported to be elevated in the plasma of those patients [ 10 - 14 ]. Involvement of the glutathionylation-dependent uncoupling of endothelial nitric oxide synthase eNOS is also reported [ 18 ].
Pharmacological intervention to oxidtive stress or RAAS are also reported. Glutathione GSH depletion by GSH synthase inhibitor buthionine sulfoximine BSO on Sprague-Dawley rats caused a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability [ 19 ].
On the contrary, activation of AT 2 receptor has shown to cause protective effects by antioxidant mechanism. Inhibition of AT 2 receptor resulted in superoxide anion production in human umbilical vein endothelial cells HUVEC , and this effect involved src homology 2 domain containing inositol phosphatases SHP-1 activation by AT 2 receptor [ 22 ].
Involvement of c-Src tyrosine kinase in SHP-1 phosphatase activation by AT 2 receptors in rat fetal tissues has been reported [ 23 ]. And authors are also suggesting AT 2 receptor-mediated inhibitory effect on oxidative stress were caused through inhibition of Akt activation brought by AT 1 receptor activation, which is a prerequisite for the AT 2 receptor to exert its inhibitory effect on NAD P H oxidase activation.
Another interesting mechanism of controlling oxidative stress is internalization of AT 1 receptor. Less Ang- 1- 7 is produced from Ang- by ACE and other alternative enzymes such as prolyl endopeptidase, neutral endopeptidase, or thimet oligopeptidase [ 27 , 28 ]. Ang- is endogenous ligand for G protein-coupled receptor GPCR Mas [ 31 ], eliciting antagonistic reaction against AT 1 receptor including vasodilation, antiproliferation in the vasculature, antihypertrophy, antifibrosis, antiarrythmia in the heart, and many other protective reactions in the kidney, and the brain etc [ 32 ].
Ang- is also reported to bind to the AT 2 receptor in in vitro experiment [ 33 ], and in vivo study, causing the AT 2 receptor-mediated effects such as increased perfusion pressure of isolated mouse hearts [ 34 ], or vasodepressor effects in rats [ 35 , 36 ]. Interestingly, Ang- has been demonstrated to bind to AT 2 receptor showing the antihypertrophic effects in adult rabbit cardiomyocytes [ 37 ]. Vasorelaxant effects caused by Ang- was reported to be mediated by prostaglandins [ 38 ], or by the endothelium-dependent release of nitric oxide, involving a B2 bradykinin receptor [ 39 ].
NO release was reported to be inhibited by the selective Mas antagonist, A, and Akt-dependent pathway was involved in NO release change, using Chinese hamster ovary cells transfected with Mas cDNA [ 40 ].
Authors report that moderate Ang- -stimulated NO release was accompanied by a very slow concomitant superoxide anion, suggesting low formation of peroxynitrite.
Thus, Ang- might preserve the vascular system, among others, due to its low formation of cytotoxic peroxynitrite by the reaction between NO and superoxide anion. As mentioned above [ 41 ], low generation of superoxide anion was reported after Ang- 1- 7 stimulation.
This may be caused from eNOS uncoupling due to L-arginine shortage [ 42 ]. Still, Mas activation causes vasodilatory and protective cardiovascular effect. One possible mechanism is Mas-mediated phosphorylation of SHP-2 [ 43 ]. Neointimal formation after cuff placement were more pronounced in Mas-knockout mice than wild-type mice.
The role of ACE2 in the vasculature is also reported, evaluating angiogenesis and atherosclerosis in endothelial cells of apoprotein E-knockout, ACE2- overexpressing and deficient mice [ 45 ]. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation. Src homology 2-containing inositol phosphatase 2. Its vasoconstrictive and pressor effect due to AT 1 receptor activation is reported [ 49 , 50 ]. By hydrolyzing the C-terminal amino acid of Ang A by ACE2, or decarboxylation of N-terminal aspartate of Ang- into alanin, alamandine is produced [ 51 ].
Alamandine produced several biological effects including endothelial-dependent vasorelaxation in aortic rings of mice and rats or central cardiovascular effects. Microinjection of alamandine into rostal ventrolateral medulla RVLM increased blood pressure, and microinjection into caudal ventrolateral medulla CVLM decreased blood pressure, and modulated the baroreflex sensitivity after intra-cerebro ventricular ICV infusion [ 51 ].
Masrelated G-coupled receptor type D MrgD has been identified as the receptor for alamandine [ 51 ]. The former causes NO production and vasorelaxation. AT 4 receptor was identified as insulin-regulated membrane aminopeptidase IRAP and was proposed that AT 4 receptor ligands may inhibit the catalytic activity of IRAP, thereby extend the half-life of its neuropeptide substrates including arginine vasopressin, oxytocin and somstostatin which are reported to enhance memory [ 61 ].
Ang- can be degraded into smaller peptides such as Ang- by ACE, neprilysin or chymase [ 64 ]. Ang- was also reported to bind AT 1 receptors, serving not only as a substrate for smaller active peptides, but also as a ligand [ 65 ]. This peptide does not exist in human tissues. The pro renin Receptor PRR is a amino acid single transmembrane receptor protein. Expressed in brain, heart, lung, liver, kidney, skeletal muscle, pancreas, fat, placenta, and others, but not in the systemic circulation. Both prorenin and renin bind to the PRR [ 66 ].
This may lead to increase oxidative stress like above-mentioned mechanism through activation of AT 1 receptor. This renin-activated pathway was reported to have triggered cell proliferation along with TGF-beta1 and plasminogen activator inhibitor-1 gene expression [ 69 ].
ATP 6 ap 2: ATPase associated protein 2. Development of novel therapeutic strategies for the better treatment of hypertension and related CVDs based on these new findings can be expected. We would like to review briefly the present status of them including experimental findings. Recombinant human ACE2 rhACE2 is reported to be a potential candidate to treat diastolic and systolic heart failure [ 73 ].
Efficacy of lentiviral vector-mediated overexpression of ACE2 is reported to inhibit the myocardial and perivascular fibrosis of experimental Ang-II infusion rat and SHR [ 74 , 75 ].
Administration of rhACE2 was well tolerated by healthy human subjects. Despite marked changes in angiotensin system peptide concentrations , cardiovascular effects were absent, suggesting the presence of effective compensatory mechanisms in healthy volunteers [ 76 ].
Efficacy of synthetic enhancers of ACE2 activators, xanthenone XNT , and resorcinolnaphthalein are reported to activate ACE2, decrease blood pressure, and reverse tissue remodeling [ 77 ], and diminazene aceturate DIZE to attenuate pulmonary hypertension in experimental models [ 78 ].
But some structural modifications are necessary for clinical use because of poor solubility in water and safety. Oral administation of Ang- seems promising as a candidate for therapy. But its clinical use is limited because of short half-life in vivo. Cyclized Ang- thioether-bridged Ang- and angiotensin- inclusion in cyclodextrin Ang- -CyD exhibited better pharmacokinetic profile in vivo but in experimental models [ 79 , 80 ]. AVE is a first synthetic non-peptide agonist for the Mas receptor and produced beneficial effects in isolated perfused rat hearts and attenuated postischemic heart failure [ 81 ].
Targeting the emerging new components of RAAS is a promising strategy for developing novel therapy for hypertension and target organ damage.
But improvement of safety and drug delivery, for example liposome modification, are necessary before future clinical application. Please leave a message, we will get back you shortly. Home Publications Conferences Register Contact. Guidelines Upcoming Special Issues. Research Article Open Access. December 20, Citation: Select your language of interest to view the total content in your interested language. Can't read the image?