Generic placeholder image

Current Vascular Pharmacology

Author(s): Vasiliki Katsi, Spyridon Maragkoudakis*, Maria Marketou, Costas Tsioufis, Fragkiskos Parthenakis and Dimitrios Tousoulis

DOI: 10.2174/1570161117666181105154843

DownloadDownload PDF Flyer Cite As
The Role of Angiotensin-(1-7)/Mas Axis and Angiotensin Type 2 Receptors in the Central Nervous System in Cardiovascular Disease and Therapeutics: A Riddle to be Solved

Page: [319 - 325] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

In recent years, the Angiotensin-(1-7)/Mas receptor [Ang-(1-7)/Mas] sub-branch of the Renin-Angiotensin System (RAS) in the brain, and Angiotensin Type 2 Receptors (AT2R), have attracted scientific interest, as there is evidence that they constitute an essential pathway in cardiovascular regulation, in health and in disease. By acting centrally, the Ang-(1-7)/Mas axis - that has been termed ‘the axis of good’- can exert blood pressure-lowering effects, while also favourably altering baroreflex sensitivity and noradrenergic neurotransmission. Thus, research has focused on the possible neuro- and cardioprotective effects of this pathway in the setting of cardiovascular disease, ultimately aiming to evaluate the potential for development of novel therapeutic strategies based on its modulation.

We summarize the available evidence from experimental studies in this context, aiming to assess current limits of scientific knowledge relevant to this newly-described ‘player’ in haemodynamic regulation, that may become a potential therapeutic target.

Keywords: Renin angiotensin system, angiotensin converting enzyme 2, angiotensin (1-7), mas receptors, angiotensin 2 receptor, hypertension, neuroprotection.

Graphical Abstract

[1]
Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin system: A target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol 2012; 302: 1219-30.
[2]
Lang CC, Struthers AD. Targeting the renin-angiotensin-aldosterone system in heart failure. Nat Rev Cardiol 2013; 10: 125-34.
[3]
Nguyen Dinh Cat A, Touyz RM. A new look at the renin-angiotensin system-focusing on the vascular system. Peptides 2011; 32: 2141-50.
[4]
Jiang F, Yang J, Zhang Y, et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: Novel therapeutic targets. Nat Rev Cardiol 2014; 11: 413-26.
[5]
De Kloet AD, Steckelings UM, Sumners C. Protective angiotensin type 2 receptors in the brain and hypertension. Curr Hypertens Rep 2017; 19: 46.
[6]
Mendoza A, Lazartigues E. The compensatory renin-angiotensin system in the central regulation of arterial pressure: New avenues and new challenges. Ther Adv Cardiovasc Dis 2015; 9: 201-8.
[7]
Santos RA, Simoes e Silva AC, Maric C, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein coupled receptor Mas. Proc Natl Acad Sci USA 2003; 100: 8258-63.
[8]
Gironacci M, Cerniello FM, Longo Carbajosa NA, Goldstein J, Cerrato BD. Protective axis of the renin-angiotensin system in the brain. Clin Sci (Lond) 2014; 127: 295-306.
[9]
Xu P, Sriramula S, Lazartigues E. ACE2/ANG-(1-7)/Mas pathway in the brain: The axis of good. Am J Physiol Regul Integr Comp Physiol 2011; 300: 804-17.
[10]
Doobay M, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2007; 292: 373-81.
[11]
Sriramula S, Cardinale JP, Lazartigues E, Francis J. ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovasc Res 2011; 92: 401-8.
[12]
Gallagher PE, Chappell MC, Ferrario CM, Tallant EA. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol 2006; 290: 420-6.
[13]
Feng Y, Xia H, Cai Y, et al. Brain-selective overexpression of human Angiotensin converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 2010; 106: 373-82.
[14]
Gurley SB, Allred A, Le TH, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006; 116: 2218-25.
[15]
Feng Y, Yue X, Xia H, et al. Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. Circ Res 2008; 102: 729-36.
[16]
Xia H, Suda S, Bindom S, et al. ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS One 2011; 6: e22682.
[17]
Oliveira DR, Santos RA, Santos GF, Khosla M, Campagnole-Santos MJ. Changes in the baroreflex control of heart rate produced by central infusion of selective angiotensin antagonists in hypertensive rats. Hypertension 1996; 27: 1284-90.
[18]
Lu J, Jiang T, Wu L, et al. The expression of angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats. Neuropeptides 2013; 47: 289-95.
[19]
Jiang T, Gao L, Shi J, Lu J, Wang Y, Zhang Y. Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats. Pharmacol Res 2013; 67: 84-9.
[20]
Tallant EA, Clark MA. Molecular mechanisms of inhibition of vascular growth by angiotensin (1-7). Hypertension 2003; 42: 574-9.
[21]
Zhang F, Hu Y, Xu Q, Ye S. Different effects of angiotensin II and angiotensin (1-7) on vascular smooth muscle cell proliferation and migration. PLoS One 2010; 5: e12323.
[22]
Wysocki J, Ye M, Rodriguez E, et al. Targeting the degradation of angiotensin II with recombinant angiotensin-converting enzyme 2: Prevention of angiotensin II-dependent hypertension. Hypertension 2010; 55: 90-8.
[23]
Kangussu LM, Guimaraes PS, Nadu AP, Melo MB, Santos RA, Campagnole-Santos MJ. Activation of angiotensin-(1-7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats. Neuropharmacology 2015; 97: 58-66.
[24]
Bennion D, Haltigan E, Regenhardt RW, Steckelings UM, Sumners C. Neuroprotective mechanisms of the ACE2-angiotensin-(1-7) - Mas axis in stroke. Curr Hypertens Rep 2015; 17: 3.
[25]
Chen J, Zhao Y, Chen S, et al. Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology 2014; 79: 550-8.
[26]
Chang AY, Li FC, Huang CW, et al. Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke. Neurobiol Dis 2014; 71: 292-304.
[27]
Chen J, Zhao Y, Chen S, et al. Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology 2014; 79: 550-8.
[28]
Lu J, Zhang Y, Shi J. Effects of intracerebroventricular infusion of angiotensin(1-7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia-reperfusion in rats. Brain Res 2008; 1219: 127-35.
[29]
Kluskens LD, Nelemans SA, Rink R, et al. Angiotensin-(1-7) with thioether bridge: An angiotensin-converting enzyme-resistant, potent angiotensin-(1-7) analog. J Pharmacol Exp Ther 2009; 328: 849-54.
[30]
Durik M, van Veghel R, Kuipers A, et al. The effect of the thioether-bridged, stabilized angiotensin-(1-7) analogue cyclic ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction. Int J Hypertens 2012; 2012: 536426.
[31]
Marques FD, Ferreira AJ, Sinisterra RD, et al. An oral formulation of angiotensin-(1-7) produces cardioprotective effects in infarcted and isoproterenol-treated rats. Hypertension 2011; 57: 477-83.
[32]
Simões e Silva AC. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol 2013; 169: 477-92.
[33]
Dai SY, Peng W, Zhang YP, Li JD, Shen Y, Sun XF. Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats. J Neuroinflammation 2015; 12: 47.
[34]
Jiang F, Yang J, Zhang Y, et al. Angiotensin converting enzyme 2 and angiotensin 1-7: Novel therapeutic targets. Nat Rev Cardiol 214(11): 413-4.
[35]
De Kloet AD, Steckelings UM, Sumners C. Protective angiotensin type 2 receptors in the brain and hypertension. Curr Hypertens Rep 2017; 19: 46.
[36]
Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci (Lond) 2011; 121: 297-303.
[37]
Villela D, Leonhardt J, Patel N, et al. Angiotensin AT2-receptor and receptor Mas: A complex liaison. Clin Sci (Lond) 2015; 128: 227-3.
[38]
Hrenak J, Paulis L, Simko F. Angiotensin A/alamandine/MrgD axis: Another clue to understanding cardiovascular pathophysiology. Int J Mol Sci 2016; 17: 1098.
[39]
Abadir PM, Periasamy A, Carey RM, Siragy HM. Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization. Hypertension 2006; 48: 316-22.
[40]
Lemos VS, Silva DM, Walther T, Alenina N, Bader M, Santos RA. The endothelium-dependent vasodilator effect of the nonpeptide Ang(1-7) mimic AVE 0991 is abolished in the aorta of mas knockout mice. J Cardiovasc Pharmacol 2005; 46: 274-9.
[41]
Banegas JR, Lopez-Garcia E, Dallongeville J, et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study. Eur Heart J 2011; 32: 2143-52.
[42]
Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high, middle and low-income countries. JAMA 2013; 310: 959-68.
[43]
Falaschetti E, Mindell J, Knott C, Poulter N. Hypertension management in England: A serial cross-sectional study from 1994 to 2011. Lancet 2014; 383: 1912-9.
[44]
Tocci G, Rosei EA, Ambrosioni E, et al. Blood pressure control in Italy: Analysis of clinical data from 2005-2011 surveys on hypertension. J Hypertens 2012; 30: 1065-74.