DOI: 10.1161/CIRCULATIONAHA.115.016328
Expanding Saga of the Renin-Angiotensin-System: The Angiotensin-II Counter-Regulatory AT2 Receptor Pathway
Running title: Jugdutt; Angiotensin-II counter-regulatory AT2 pathway
Bodh I. Jugdutt, MD, DM, FRCPC, FACC, FAHA
Cardiology Division of the Department of Medicine, Faculty of Medicine, University Universiity off Alberta, Albberta Al Albe bert be r a, Canada Edmonton, Al Alberta,
Addr Ad dres dr esss for es for Correspondence: Corr Co rres rr espo es pond po nden nd ence en ce:: ce Address Bodh II.. Ju Jugd gdut utt, t M D DM D, DM, FR FRCP CPC, C F ACC, AC C FAHA FAH AHA A Bodh Jugdutt, MD, FRCPC, FACC, Division of Cardiology, University of Alberta 2C2 Walter MacKenzie Health Sciences Centre Edmonton, Alberta, T6G 2R7, Canada Tel: 780-439-0745 Fax: 780-437-3546 E-mail: [email protected]
Journal Subject Code: Hypertension:[115] Remodeling
Key words: Editorial, angiotensin; hypertension; peptides, receptors, renin-angiotensin-system
1
DOI: 10.1161/CIRCULATIONAHA.115.016328
The search for hidden truths behind established concepts and dogma is often a never-ending, uphill climb and the history of Science and Medicine is full of examples of this. “To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advances in science” (Albert Einstein). The story of the reninangiotensin system (RAS), hypertension and kidney disease began nearly two centuries ago,1 with report of a clinico-pathophysiologic study of albuminuria in patients followed by Goldblatt’s induction of hypertension in experimental dogs in the 1930’s.2 It took seven more decades of basic, translational and clinical research to discover the pressor effect of renal extracts (ascribed to renin) in 1898 and another ten decades of imaginative work by many to culminate in he discovery of angiotensin-II (Ang-II), the primary effector peptide of the RAS, S,, aand nd iits ts the eceptors (AT1R and AT2R) in 2000.3 Since then, expansion of the RAS to the renin-angiotensinreceptors alldo ost steeron eronne (R (RAA AA AS) S system and discovery of se eve v ral bioactive peptides peept p id des produced produced through Angaldosterone (RAAS) several III ddegradation e radationn hhas eg as con contributed onntrrib ibut uted ted tto o th thee in increasing ncreassinng com complexity omplex om exit ex ityy ooff tthe he R he RAS AS (Figures (Fi Figu gure gu ress 1A aand1B) nd1B nd 1B)) and 1B and the he se search ear a ch ccontinues. onti on tinnue nues. e s. Sincee the the 11990’s, 990’ 99 0 s, s therapy the hera he r py bbased ra ased as d oon n in inhi inhibition h bi hi biti t on ooff th ti thee ef effe effects fect fe c s of A ct Ang-II ng-I ng -III wi with th A ACEC CE inhibitors and AT1R blockers has dominated the experimental and clinical research arenas. Cumulative evidence indicated that the RAS, through Ang-II generated primarily by the angiotensin-converting enzyme (ACE), plays a critical role in the regulation of blood pressure, fluid and electrolyte balance, cardiovascular and renal homeostasis, and pathophysiology of hypertension and cardiovascular and renal disease.4,5 Angiotensin-II was implicated in increased blood pressure and vascular remodeling with vascular inflammation, endothelial dysfunction, atherosclerosis and smooth muscle hypertrophy as well as cardiac remodeling with myocardial fibrosis and hypertrophy leading to diastolic and systolic heart failure.4,5 Angiotensin-II was
2
DOI: 10.1161/CIRCULATIONAHA.115.016328
shown to stimulate release of aldosterone which in turn stimulates inflammation, fibrosis and cardiovascular remodeling (Figure 1A). Evidence that most of the effects of Ang-II are mediated via AT1 receptors provided the rationale for use of ACE-inhibition and AT1 receptor blockade (Figure 1). Evidence that ACE-inhibitors do not block AngII generated via non-ACE pathways in cardiovascular and other tissues,6 the ability of AT1R blockers to selectively block Ang-II at the AT1R thereby producing more complete inhibition was considered advantageous (Figure 1A). Although ACE-inhibitors increase bradykinin by suppressing its degradation thereby enhancing vasodilation, this benefit may be offset by a nearly 20% risk of troublesome cough and angioneurotic edema.5 However, AT1R blockers may also result in enhanced vasodilation via unopposed AT2R activation and downstream AT2-mediated signaling.5 Other ev evidence vid den ncee iindicates ndic nd icat ic ates e that hat ARBs can also release kinins and increase bradykinin levels in hypertensive patients,7which may au may augm gm men e t benefits beene nefi fits that are offset by the riskk of of cough and angioedema. ang nggio i ed dema. Randomized clinical augment trials rialls ls (RCTs) mounted mo ounte tedd too resolve res esol olvve well-known ol well we ll-k -knnow wn arguments wn arg gum umen ntss for for using usi sinng ng AT AT1R blockers bloc bl ocke oc kers rss have hav a e shown show sh ow wn benefits be enefi nefi fits t of ts of bo both th ACE-inhibitors ACECE-innhib nhibittors an andd A AT T1R blockers bloc ocke oc keerss fo for or ccontrolling or ontr on trol olli ol ling ng bblood lo ood d pressure pre ress sssur uree in 8 10 hypertension n.8-10 A downside dow owns nsid idee off cchronic id hron hr o ic A ACE-inhibitor CE-i CE -iinh nhib ib bit itor or ttherapy herrap he apyy in i hheart eart ea rt ffailure ailu ai l ree ppatients lu a ie at ient n s is that nt hypertension.
AngII levels increase and symptoms worsen.5 Importantly, aging is associated with RAS dysregulation and increased Ang-II and other RAS components which in turn may contribute to increased cardiovascular remodeling and risk in elderly patients.4,5 In diabetic nephropathy, excessive RAAS activation results in progressive renal damage.11 Up until a decade ago, the collective evidence favored the concept of a regulatory arm of the RAS with an ACE/Ang-II/AT1 R axis that mediates vasoconstriction whereas under AT1 R blockade, the AT2R mediates vasodilation (Figure 1A). Evidence over the last decade, unraveled existence of a counter-regulatory arm of the RAS via an Ang-(1-7)/ACE-2/mas receptor axis that
3
DOI: 10.1161/CIRCULATIONAHA.115.016328
vasoconstrictor, proliferative, profibrotic and prothrombotic actions of Ang-II (Figures 1A and 1B).12,13 The Ang-(1-7)/Mas axis regulates several signaling pathways, such as PI3K (phosphoinositide 3-kinase)/AKT and ERK (extracellular-signal-regulated kinase) pathways and involves downstream effectors such as NO (nitric oxide), FOXO1 (forkhead box O1) and COX-2 (cyclooxygenase-2). In the counter-regulatory and vasodepressor arm, both ACE-inhibitors and AT1 receptor blockers can increase angiotensin-(1-7).5,10 This axis is a potential therapeutic target in cardio-renal disease. In summary, RAAS blockade with ACE-inhibitors or AT1R blockers is standard recommended therapy for hypertension, heart failure and non-diabetic/diabetic chronic renal disease, and aldosterone blockade is used in selected patients.5,9-11 Clinicians recognize reccogni n zee tthat ni hatt ha optimal therapy is critical for survival with a favorable outcome and combination therapies are often offteen need nneeded. eed eded ed.. Ov ed Over ver tthe he last two decades, severall la llaboratories boratories hav have ve been en n ssearching e rching for specific ea molecular mollecular le targets targ get etss tthat hat at may may ay llead eadd to ea o tthe h ddevelopment he evelloppmen nt off therapies thera heraapies and annd nd strategies strattegi giiess to to optimize o ti op tim mize therapy prevent adverse remodeling her erap apyy of hhypertension, ap yperte yper tens n io ns on,, hheart eart ea r ffailure rt ailu ai lurre lu re aand ndd cchronic hron onic on icc rrenal enal ddisease, isea is ease se,, pr se prev even ev en nt ad adve vers ve rsse re rem modeli mod deli l ngg aand nd nd improve mprove outc outcome. com ome. e.. M Many anyy st an studies tud udie iess ha hhave v bbeen ve eenn co ee cond conducted nduc nd ucte teed in n eexperimental xper xp errim imen nta tall an anim animal imal im al m models odel od elss and el humans. However, therapy to limit adverse remodeling in patients with these diseases, especially the elderly remains suboptimal, and hearts continue to enlarge after hypertension and heart failure. In this issue of Circulation, Jankowski and colleagues tested the provocative and bold hypothesis that a novel peptide acts as an endogenous cofactor in Ang-II-mediated vasoregulatory effects. The observation that plasma Ang-II concentrations were not increased in patients with heart failure and chronic kidney disease14 triggered the idea that unknown endogenous cofactors may be involved in the action of Ang-II.15 They present a large volume of
4
DOI: 10.1161/CIRCULATIONAHA.115.016328
compelling data suggesting that this peptide, a fragment of chromogranin-A that they named ‘vasoconstriction inhibiting factor (VIF)’ modulates vasoconstrictive effects of Ang-II and exerts vasodilator effects mediated by AT2R, and may provide a potential counter-regulatory mechanism against hypertension.15 This interesting non-RAS peptide acting through AT2R further underscores the complexity of the RAS/RAAS (Figure 1B) and need for more research to establish its importance as a potential target for the prevention and therapy of cardiovascular disease. Marie Curie, winner of separate Nobel Prizes for Physics and Chemistry, is credited with saying “be more curious about ideas.” It is known that chromogranin-A is produced by chromaffin cells of the adrenal medulla and other tissues and is elevated in pheochromocytomas. It serves as precursor to to several seeve vera rall functional peptides including vasostatin-I, vasostatin-II, pancreastatin, catestatin and parastatin whic wh ichh negatively ic nega nega gati tivvely ti ly y modulate modulate autocrine and paracrine paracrrin inee functions.16-18 Som Some me ooff these peptides such as which vvasostatin-I asoostatin-I and ndd vasostatin-II vasos ossta tati tinti n III inhibit ninhi hibi bitt vasoconstriction bi vasocons nsstricttioon w while hilee cconcentrations hile onccent on centra rati t ons of ccatestatin ti ateesta at tati ta tinn are ti a re reduced patients. Here edu duce cedd and ce an nd those thosse of chromogranin-A thos chrrom omog ogra og raani ninn-A A are arre increased incrrea in e se sedd inn hypertensive hyp yper erte tens te nssiv ve pa atieents entss. He H re JJankowski an nkoows wsk ki eett al14 report att lleast east ea stt sseven e en imp ev important mpor mp o taant n findings. find fi nddin i gs g . Fi F First, r t, rs t tthey heyy ni he nice nicely cely ce ly ddemonstrated emo mons nstr ns trat tr ated at ed tthat hatt VI ha VIF F re rreleased leased from the adrenal glands and derived from chromogranin-A modulates Ang-II induced vasoconstriction by testing different VIF concentrations on AngII-induced vasoconstriction and calculating the EC50. Second, they probed mechanisms and showed that VIF impairs AngIIinduced phosphorylation of p38MAPK but not ERK1/2. Third, they present evidence suggesting that elevated plasma VIF may modulate the harmful effects of Ang-II in chronic renal disease and heart failure patients especially chromogranin-A is also elevated in these patients. Fourth, they showed that VIF reduced Ang-II-induced increase in blood pressure in vivo. Fifth, they confirmed absence of homology in aminoacid sequences between VIF and the other main Ang
5
DOI: 10.1161/CIRCULATIONAHA.115.016328
peptides. Sixth, they confirmed VIF but neither scrambled nor truncated peptides caused a significant effect on AngII-induced vasoconstriction. Seventh, they addressed the affinity of VIF for AT2R by showing that VIF inhibits AngII-induced vasoconstriction in a large physiologically relevant range, maintains its effect in the presence of L-NAME (hence independent of NO) but its effect is abolished by the AT2R blocker PD 123,319. These findings unmasking the NOindependent effect of VIF on the AT2 receptors further underscore the importance of AT2R in the regulation of blood pressure. The overall findings of Jankowski et al14 underscore the complexity of vasoregulation as pointed out by the authors. Importantly, the findings suggest a potentially novel strategy for promoting counterregulatory vasodilation thereby limiting hypertension, adver adverse rse rremodeling emod em odel od elin el ingg in and heart failure. Whether targeting the VIF/AT2R pathway might be a potential approach for pr rev ven nti ting ngg aadverse dver errse rremodeling emodeling and improving ou out tcome in hypert ten e sion on nw arrants study. Whether preventing outcome hypertension warrants VIF V IF F levels aree ddecreased ecreas ecre assed dw with ithh ag it agin aging in ng and an nd exp explains plaains the thhe poorer poore rerr outcome outccome in outc in older old derr patients pattie i nt n s also allso so deserves dese de serv se rves rv e sstudy. es tudy tu dy. Th Thee au authors uth hor ors de ddeserve serv se rvee to rv o bbee ap appl applauded pllau a ded ded for for th thee id idea eaa tthat hatt nnon-RAS ha onn-RA n-RA RAS S de derived eri rive vedd pept ppeptide epttid de may interactt with witth one one orr more mor oree of the the three thr hree hr ee major majo ma jorr RAS jo RAS receptors rece re cept ce ptor pt orss (AT1R, or (A AT1 T1R, R A R, AT2R, T R, aand T2 nd M Mas) as) and produce significant physiological and pathophysiological effects. This possibility opens upon a new area of research into other biologically active peptides. The authors have suggested testing for interactions of VIF with other angiotensin peptides [such as angiotensinogen, Ang-II, AngIII, Ang-IV, and Ang-(1-7)], angioprotectin and alamandine.14 However, the possibility that peptide interactions may not always be beneficial but rather might be harmful and contribute to disease progression should also be considered.
6
DOI: 10.1161/CIRCULATIONAHA.115.016328
Funding Sources: This work was in part by grant support to 2012 (IAP99003) from the Canadian Institutes of Health Research.
Conflict of Interest Disclosures: None.
References: 1. Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001;38:1246-1249. 2. Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension, I: the production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med. 1934;59:347-379. 3. de Gasparo p M,, Catt KJ,, Inagami g T,, Wright g JW,, Unger g T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacolog Rev. 2000;52:415-472. 2000;52: 2:41 41541 5-47 5472. 47 2 2. 4. Jugdutt BI. Aging and Remodeling of the RAS and RAAS and Related Pathways: Implication Implications for Heart Failure Therapy. In, Jugdutt BI, Ed. Aging and Heart Failure: Mechanisms and Management.Springer Ma anaage geme ment me ntt.Sppri ring n er 2014, pp 259-289. ng Juugdutt ug BI. I Clinical Cli lini n caal effectiveness efffec eff fectiv ctiv iven enes en e s of telmisartan es tel elmi misa mi saart rtan n alone alone ne or or in in combination comb co mbin mb inaatio in ation therapy th her erap apyy fo ap or 5.. Jugdutt BI. for controlling cco ontrolling nt bloodd pressure presssuure and and vascular vasc scuulaar risk riskk inn thee elderly. elder erly ly.. Cl ly Clin lin IInterv nterv Ag Agin Aging. ingg. 20 2010 2010;5:403-416. 100;5 5:4 4033-4 416.. 6. 6 Urata Ura rata ta H, H, Healy Heal Heal alyy B, B Stewart Ste tewa w rtt R.W, wa R.W .W, W Bumpus Bump Bu mpuus mp us F.M, F.M M, Husain Husa Hu saain A. A. Angiotensin-II-forming Angi Angi giot oten ot en nsi sinn II nII-f -ffor ormi ming mi ng ppathways athw at hway hw ayss in ay normal norm no rmal rm al aand nd ffailing aili ai ling li ng hhuman uman um an hhearts. eart ea rtss. Circ rt Circ R Res.1990;66:883-890. es.199 199 990; 0;66 0; 66:8 66 :883 :8 83-8 -890 890 90. 7. Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111:315-320. 8. Kjeldsen SE, Lyle PA, Tershakovec AM, et al. Targeting the renin-angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Expert Opin Emerg Drugs. 2005;10:729-745. 9. Go AS, Bauman MA, King SMC, Fonarow GC, Lawrence W, Williams KA, Sanchez E. An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension. 2014;63:878-885. 10. Jugdutt BI. Valsartan in the treatment of heart attack survivors. Vasc Health Risk Manag. 2006;2:125-138. 11. Ferrario CM..ACE2: more of Ang-(1-7) or less Ang II? Curr Opin Nephrol Hypertens. 2011;20:1-6.
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12. Passos-Silva DG, Verano-Braga DG, Santos RA. Angiotensin-(1-7): beyond the cardio-renal actions. Clin Sci (Lond). 2013;124:443-456. 13. Roscioni SS, Heerspink HJ, de Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephrol. 2014;10:77-87. Erratum. Nat Rev Nephrol. 2014;10:243. 14. Jankowski J, Salem S, Jankowski V, Asare Y, Liehn E, Welker P, Raya-Bermudez A, Pineda C, Rodriguez M, Muñoz-Castañeda J, Bruck H, Marx N, Machado F, Staudt M, Heinze G, Zidek W. The identification of the “vasoconstriction inhibiting factor” (VIF), a potent endogenous cofactor of angiotensin II acting on the AT2 receptor. Circulation. 2015;131:XXXXX. 15. Jankowski V, Tolle M, Santos RA, Gunthner T, Krause E, Beyermann M, Welker P, Bader M, Pinheiro SV, Sampaio WO, Lautner R, Kretschmer A, van der Giet M, Zidek W, Jankowski J. Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects. FASEB J. 2011;25:2987-2995. susceptibility 16. Sahu BS, Sonawane PJ, Mahapatra NR. Chromogranin A: a novel susceptibilit ityy ge ggene ne ffor or essential hypertension. Cell Mol Life Sci. 2011;67:861-874. 17. Roatta S, Passatore M, Novello M, Colombo B, Dondossola E, Mohammed M, Losano G, Corti A, Helle KB. The chromogranin A- derived N-terminal peptide vasostatin-I: In vivo effects ef ffeect ctss onn cardiovascular carrdiov ov vascular as variables in the rabbit. Regul Regul Pept. 2011;168:10-20. Reg 20111;1 ; 688:1 :100-20. Tota Quintieri Felice V,, C Cerra MC. New biological chromogranin 118. 8. T ota B, Qu uin intiier erii AM AM, Di F elic el icee V ic errra MC C. N ew w bi bio ologic ogiccall aaspects sppec ects ts ooff ch chro ro omog mogran aniin in A-derived peptides: focus Comp Biochem Mol Physiol. A -dderived de pept pe p id dess: fo ocu us onn vasostatins. vassossta tatiinss. Co o mp B io och chem em Physiol Phyysiool A M ol Integr ol Integ gr Ph hys ysio ioll. 2007;147:11-18. 20 007 07;1 ;147 ;1 47:1 :1 111-18 18..
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Figure Legend:
Figure 1. A. Major pathways in the RAS and RAAS cascades. ACE, angiotensin-converting enzyme; ACE-I, ACE-inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; cGMP, cyclic guanosine 3c 5c monophosphate; EDHF, endothelin-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; MRA, mineralocorticoid receptor antagonist; PAI-1, plasminogen activator inhibitor-1; PGI2, prostacyclin; PKCH, protein kinase CH; RAS, reninangiotensin system; RAAS, renin-angiotensin-aldosterone system; t-PA, tissue plasminogen activator. B. Enzymatic cascades and key receptor activation pathways in the RAS. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang,, angi aangiotensin; ngi g oten oten ensi sin; si n; AT1R and AT2R, Ang-II type 1 and type 2 receptor respectively; Mas R, Ang 1-7 receptor; VIF, vasoconstriction vaso soco constric icttion iinhibiting nhibiting factor. Angiotensinoge Angiotensinogen, en, angiotensin III, I, ang angiotensin gio iotensin III, angiotensin IV, V, and angiotensin angioten nsinn -(1–7) -(1––7) are are the main main in biologically biolloggicalllyy active accti tivee peptides peeptiidees off RAS. RAS S. VIF VIF is a non-RAS non-R RAS peptide pept ptid idee th that at acts actts via via AT2R. R 155
9
Figure 1A
Figure 1B
Expanding Saga of the Renin-Angiotensin-System: The Angiotensin-II Counter-Regulatory AT2 Receptor Pathway
Running title: Jugdutt; Angiotensin-II counter-regulatory AT2 pathway
Bodh I. Jugdutt, MD, DM, FRCPC, FACC, FAHA
Cardiology Division of the Department of Medicine, Faculty of Medicine, University Universiity off Alberta, Albberta Al Albe bert be r a, Canada Edmonton, Al Alberta,
Addr Ad dres dr esss for es for Correspondence: Corr Co rres rr espo es pond po nden nd ence en ce:: ce Address Bodh II.. Ju Jugd gdut utt, t M D DM D, DM, FR FRCP CPC, C F ACC, AC C FAHA FAH AHA A Bodh Jugdutt, MD, FRCPC, FACC, Division of Cardiology, University of Alberta 2C2 Walter MacKenzie Health Sciences Centre Edmonton, Alberta, T6G 2R7, Canada Tel: 780-439-0745 Fax: 780-437-3546 E-mail: [email protected]
Journal Subject Code: Hypertension:[115] Remodeling
Key words: Editorial, angiotensin; hypertension; peptides, receptors, renin-angiotensin-system
1
DOI: 10.1161/CIRCULATIONAHA.115.016328
The search for hidden truths behind established concepts and dogma is often a never-ending, uphill climb and the history of Science and Medicine is full of examples of this. “To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advances in science” (Albert Einstein). The story of the reninangiotensin system (RAS), hypertension and kidney disease began nearly two centuries ago,1 with report of a clinico-pathophysiologic study of albuminuria in patients followed by Goldblatt’s induction of hypertension in experimental dogs in the 1930’s.2 It took seven more decades of basic, translational and clinical research to discover the pressor effect of renal extracts (ascribed to renin) in 1898 and another ten decades of imaginative work by many to culminate in he discovery of angiotensin-II (Ang-II), the primary effector peptide of the RAS, S,, aand nd iits ts the eceptors (AT1R and AT2R) in 2000.3 Since then, expansion of the RAS to the renin-angiotensinreceptors alldo ost steeron eronne (R (RAA AA AS) S system and discovery of se eve v ral bioactive peptides peept p id des produced produced through Angaldosterone (RAAS) several III ddegradation e radationn hhas eg as con contributed onntrrib ibut uted ted tto o th thee in increasing ncreassinng com complexity omplex om exit ex ityy ooff tthe he R he RAS AS (Figures (Fi Figu gure gu ress 1A aand1B) nd1B nd 1B)) and 1B and the he se search ear a ch ccontinues. onti on tinnue nues. e s. Sincee the the 11990’s, 990’ 99 0 s, s therapy the hera he r py bbased ra ased as d oon n in inhi inhibition h bi hi biti t on ooff th ti thee ef effe effects fect fe c s of A ct Ang-II ng-I ng -III wi with th A ACEC CE inhibitors and AT1R blockers has dominated the experimental and clinical research arenas. Cumulative evidence indicated that the RAS, through Ang-II generated primarily by the angiotensin-converting enzyme (ACE), plays a critical role in the regulation of blood pressure, fluid and electrolyte balance, cardiovascular and renal homeostasis, and pathophysiology of hypertension and cardiovascular and renal disease.4,5 Angiotensin-II was implicated in increased blood pressure and vascular remodeling with vascular inflammation, endothelial dysfunction, atherosclerosis and smooth muscle hypertrophy as well as cardiac remodeling with myocardial fibrosis and hypertrophy leading to diastolic and systolic heart failure.4,5 Angiotensin-II was
2
DOI: 10.1161/CIRCULATIONAHA.115.016328
shown to stimulate release of aldosterone which in turn stimulates inflammation, fibrosis and cardiovascular remodeling (Figure 1A). Evidence that most of the effects of Ang-II are mediated via AT1 receptors provided the rationale for use of ACE-inhibition and AT1 receptor blockade (Figure 1). Evidence that ACE-inhibitors do not block AngII generated via non-ACE pathways in cardiovascular and other tissues,6 the ability of AT1R blockers to selectively block Ang-II at the AT1R thereby producing more complete inhibition was considered advantageous (Figure 1A). Although ACE-inhibitors increase bradykinin by suppressing its degradation thereby enhancing vasodilation, this benefit may be offset by a nearly 20% risk of troublesome cough and angioneurotic edema.5 However, AT1R blockers may also result in enhanced vasodilation via unopposed AT2R activation and downstream AT2-mediated signaling.5 Other ev evidence vid den ncee iindicates ndic nd icat ic ates e that hat ARBs can also release kinins and increase bradykinin levels in hypertensive patients,7which may au may augm gm men e t benefits beene nefi fits that are offset by the riskk of of cough and angioedema. ang nggio i ed dema. Randomized clinical augment trials rialls ls (RCTs) mounted mo ounte tedd too resolve res esol olvve well-known ol well we ll-k -knnow wn arguments wn arg gum umen ntss for for using usi sinng ng AT AT1R blockers bloc bl ocke oc kers rss have hav a e shown show sh ow wn benefits be enefi nefi fits t of ts of bo both th ACE-inhibitors ACECE-innhib nhibittors an andd A AT T1R blockers bloc ocke oc keerss fo for or ccontrolling or ontr on trol olli ol ling ng bblood lo ood d pressure pre ress sssur uree in 8 10 hypertension n.8-10 A downside dow owns nsid idee off cchronic id hron hr o ic A ACE-inhibitor CE-i CE -iinh nhib ib bit itor or ttherapy herrap he apyy in i hheart eart ea rt ffailure ailu ai l ree ppatients lu a ie at ient n s is that nt hypertension.
AngII levels increase and symptoms worsen.5 Importantly, aging is associated with RAS dysregulation and increased Ang-II and other RAS components which in turn may contribute to increased cardiovascular remodeling and risk in elderly patients.4,5 In diabetic nephropathy, excessive RAAS activation results in progressive renal damage.11 Up until a decade ago, the collective evidence favored the concept of a regulatory arm of the RAS with an ACE/Ang-II/AT1 R axis that mediates vasoconstriction whereas under AT1 R blockade, the AT2R mediates vasodilation (Figure 1A). Evidence over the last decade, unraveled existence of a counter-regulatory arm of the RAS via an Ang-(1-7)/ACE-2/mas receptor axis that
3
DOI: 10.1161/CIRCULATIONAHA.115.016328
vasoconstrictor, proliferative, profibrotic and prothrombotic actions of Ang-II (Figures 1A and 1B).12,13 The Ang-(1-7)/Mas axis regulates several signaling pathways, such as PI3K (phosphoinositide 3-kinase)/AKT and ERK (extracellular-signal-regulated kinase) pathways and involves downstream effectors such as NO (nitric oxide), FOXO1 (forkhead box O1) and COX-2 (cyclooxygenase-2). In the counter-regulatory and vasodepressor arm, both ACE-inhibitors and AT1 receptor blockers can increase angiotensin-(1-7).5,10 This axis is a potential therapeutic target in cardio-renal disease. In summary, RAAS blockade with ACE-inhibitors or AT1R blockers is standard recommended therapy for hypertension, heart failure and non-diabetic/diabetic chronic renal disease, and aldosterone blockade is used in selected patients.5,9-11 Clinicians recognize reccogni n zee tthat ni hatt ha optimal therapy is critical for survival with a favorable outcome and combination therapies are often offteen need nneeded. eed eded ed.. Ov ed Over ver tthe he last two decades, severall la llaboratories boratories hav have ve been en n ssearching e rching for specific ea molecular mollecular le targets targ get etss tthat hat at may may ay llead eadd to ea o tthe h ddevelopment he evelloppmen nt off therapies thera heraapies and annd nd strategies strattegi giiess to to optimize o ti op tim mize therapy prevent adverse remodeling her erap apyy of hhypertension, ap yperte yper tens n io ns on,, hheart eart ea r ffailure rt ailu ai lurre lu re aand ndd cchronic hron onic on icc rrenal enal ddisease, isea is ease se,, pr se prev even ev en nt ad adve vers ve rsse re rem modeli mod deli l ngg aand nd nd improve mprove outc outcome. com ome. e.. M Many anyy st an studies tud udie iess ha hhave v bbeen ve eenn co ee cond conducted nduc nd ucte teed in n eexperimental xper xp errim imen nta tall an anim animal imal im al m models odel od elss and el humans. However, therapy to limit adverse remodeling in patients with these diseases, especially the elderly remains suboptimal, and hearts continue to enlarge after hypertension and heart failure. In this issue of Circulation, Jankowski and colleagues tested the provocative and bold hypothesis that a novel peptide acts as an endogenous cofactor in Ang-II-mediated vasoregulatory effects. The observation that plasma Ang-II concentrations were not increased in patients with heart failure and chronic kidney disease14 triggered the idea that unknown endogenous cofactors may be involved in the action of Ang-II.15 They present a large volume of
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DOI: 10.1161/CIRCULATIONAHA.115.016328
compelling data suggesting that this peptide, a fragment of chromogranin-A that they named ‘vasoconstriction inhibiting factor (VIF)’ modulates vasoconstrictive effects of Ang-II and exerts vasodilator effects mediated by AT2R, and may provide a potential counter-regulatory mechanism against hypertension.15 This interesting non-RAS peptide acting through AT2R further underscores the complexity of the RAS/RAAS (Figure 1B) and need for more research to establish its importance as a potential target for the prevention and therapy of cardiovascular disease. Marie Curie, winner of separate Nobel Prizes for Physics and Chemistry, is credited with saying “be more curious about ideas.” It is known that chromogranin-A is produced by chromaffin cells of the adrenal medulla and other tissues and is elevated in pheochromocytomas. It serves as precursor to to several seeve vera rall functional peptides including vasostatin-I, vasostatin-II, pancreastatin, catestatin and parastatin whic wh ichh negatively ic nega nega gati tivvely ti ly y modulate modulate autocrine and paracrine paracrrin inee functions.16-18 Som Some me ooff these peptides such as which vvasostatin-I asoostatin-I and ndd vasostatin-II vasos ossta tati tinti n III inhibit ninhi hibi bitt vasoconstriction bi vasocons nsstricttioon w while hilee cconcentrations hile onccent on centra rati t ons of ccatestatin ti ateesta at tati ta tinn are ti a re reduced patients. Here edu duce cedd and ce an nd those thosse of chromogranin-A thos chrrom omog ogra og raani ninn-A A are arre increased incrrea in e se sedd inn hypertensive hyp yper erte tens te nssiv ve pa atieents entss. He H re JJankowski an nkoows wsk ki eett al14 report att lleast east ea stt sseven e en imp ev important mpor mp o taant n findings. find fi nddin i gs g . Fi F First, r t, rs t tthey heyy ni he nice nicely cely ce ly ddemonstrated emo mons nstr ns trat tr ated at ed tthat hatt VI ha VIF F re rreleased leased from the adrenal glands and derived from chromogranin-A modulates Ang-II induced vasoconstriction by testing different VIF concentrations on AngII-induced vasoconstriction and calculating the EC50. Second, they probed mechanisms and showed that VIF impairs AngIIinduced phosphorylation of p38MAPK but not ERK1/2. Third, they present evidence suggesting that elevated plasma VIF may modulate the harmful effects of Ang-II in chronic renal disease and heart failure patients especially chromogranin-A is also elevated in these patients. Fourth, they showed that VIF reduced Ang-II-induced increase in blood pressure in vivo. Fifth, they confirmed absence of homology in aminoacid sequences between VIF and the other main Ang
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peptides. Sixth, they confirmed VIF but neither scrambled nor truncated peptides caused a significant effect on AngII-induced vasoconstriction. Seventh, they addressed the affinity of VIF for AT2R by showing that VIF inhibits AngII-induced vasoconstriction in a large physiologically relevant range, maintains its effect in the presence of L-NAME (hence independent of NO) but its effect is abolished by the AT2R blocker PD 123,319. These findings unmasking the NOindependent effect of VIF on the AT2 receptors further underscore the importance of AT2R in the regulation of blood pressure. The overall findings of Jankowski et al14 underscore the complexity of vasoregulation as pointed out by the authors. Importantly, the findings suggest a potentially novel strategy for promoting counterregulatory vasodilation thereby limiting hypertension, adver adverse rse rremodeling emod em odel od elin el ingg in and heart failure. Whether targeting the VIF/AT2R pathway might be a potential approach for pr rev ven nti ting ngg aadverse dver errse rremodeling emodeling and improving ou out tcome in hypert ten e sion on nw arrants study. Whether preventing outcome hypertension warrants VIF V IF F levels aree ddecreased ecreas ecre assed dw with ithh ag it agin aging in ng and an nd exp explains plaains the thhe poorer poore rerr outcome outccome in outc in older old derr patients pattie i nt n s also allso so deserves dese de serv se rves rv e sstudy. es tudy tu dy. Th Thee au authors uth hor ors de ddeserve serv se rvee to rv o bbee ap appl applauded pllau a ded ded for for th thee id idea eaa tthat hatt nnon-RAS ha onn-RA n-RA RAS S de derived eri rive vedd pept ppeptide epttid de may interactt with witth one one orr more mor oree of the the three thr hree hr ee major majo ma jorr RAS jo RAS receptors rece re cept ce ptor pt orss (AT1R, or (A AT1 T1R, R A R, AT2R, T R, aand T2 nd M Mas) as) and produce significant physiological and pathophysiological effects. This possibility opens upon a new area of research into other biologically active peptides. The authors have suggested testing for interactions of VIF with other angiotensin peptides [such as angiotensinogen, Ang-II, AngIII, Ang-IV, and Ang-(1-7)], angioprotectin and alamandine.14 However, the possibility that peptide interactions may not always be beneficial but rather might be harmful and contribute to disease progression should also be considered.
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Funding Sources: This work was in part by grant support to 2012 (IAP99003) from the Canadian Institutes of Health Research.
Conflict of Interest Disclosures: None.
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12. Passos-Silva DG, Verano-Braga DG, Santos RA. Angiotensin-(1-7): beyond the cardio-renal actions. Clin Sci (Lond). 2013;124:443-456. 13. Roscioni SS, Heerspink HJ, de Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephrol. 2014;10:77-87. Erratum. Nat Rev Nephrol. 2014;10:243. 14. Jankowski J, Salem S, Jankowski V, Asare Y, Liehn E, Welker P, Raya-Bermudez A, Pineda C, Rodriguez M, Muñoz-Castañeda J, Bruck H, Marx N, Machado F, Staudt M, Heinze G, Zidek W. The identification of the “vasoconstriction inhibiting factor” (VIF), a potent endogenous cofactor of angiotensin II acting on the AT2 receptor. Circulation. 2015;131:XXXXX. 15. Jankowski V, Tolle M, Santos RA, Gunthner T, Krause E, Beyermann M, Welker P, Bader M, Pinheiro SV, Sampaio WO, Lautner R, Kretschmer A, van der Giet M, Zidek W, Jankowski J. Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects. FASEB J. 2011;25:2987-2995. susceptibility 16. Sahu BS, Sonawane PJ, Mahapatra NR. Chromogranin A: a novel susceptibilit ityy ge ggene ne ffor or essential hypertension. Cell Mol Life Sci. 2011;67:861-874. 17. Roatta S, Passatore M, Novello M, Colombo B, Dondossola E, Mohammed M, Losano G, Corti A, Helle KB. The chromogranin A- derived N-terminal peptide vasostatin-I: In vivo effects ef ffeect ctss onn cardiovascular carrdiov ov vascular as variables in the rabbit. Regul Regul Pept. 2011;168:10-20. Reg 20111;1 ; 688:1 :100-20. Tota Quintieri Felice V,, C Cerra MC. New biological chromogranin 118. 8. T ota B, Qu uin intiier erii AM AM, Di F elic el icee V ic errra MC C. N ew w bi bio ologic ogiccall aaspects sppec ects ts ooff ch chro ro omog mogran aniin in A-derived peptides: focus Comp Biochem Mol Physiol. A -dderived de pept pe p id dess: fo ocu us onn vasostatins. vassossta tatiinss. Co o mp B io och chem em Physiol Phyysiool A M ol Integr ol Integ gr Ph hys ysio ioll. 2007;147:11-18. 20 007 07;1 ;147 ;1 47:1 :1 111-18 18..
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Figure Legend:
Figure 1. A. Major pathways in the RAS and RAAS cascades. ACE, angiotensin-converting enzyme; ACE-I, ACE-inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; cGMP, cyclic guanosine 3c 5c monophosphate; EDHF, endothelin-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; MRA, mineralocorticoid receptor antagonist; PAI-1, plasminogen activator inhibitor-1; PGI2, prostacyclin; PKCH, protein kinase CH; RAS, reninangiotensin system; RAAS, renin-angiotensin-aldosterone system; t-PA, tissue plasminogen activator. B. Enzymatic cascades and key receptor activation pathways in the RAS. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang,, angi aangiotensin; ngi g oten oten ensi sin; si n; AT1R and AT2R, Ang-II type 1 and type 2 receptor respectively; Mas R, Ang 1-7 receptor; VIF, vasoconstriction vaso soco constric icttion iinhibiting nhibiting factor. Angiotensinoge Angiotensinogen, en, angiotensin III, I, ang angiotensin gio iotensin III, angiotensin IV, V, and angiotensin angioten nsinn -(1–7) -(1––7) are are the main main in biologically biolloggicalllyy active accti tivee peptides peeptiidees off RAS. RAS S. VIF VIF is a non-RAS non-R RAS peptide pept ptid idee th that at acts actts via via AT2R. R 155
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Figure 1A
Figure 1B
