Current Hypertension Reports

, Volume 14, Issue 5, pp 403–409 | Cite as

Impact of the AT2 Receptor Agonist C21 on Blood Pressure and Beyond

  • Sébastien Foulquier
  • U. Muscha Steckelings
  • Thomas Unger
Antihypertensive Therapy: Patient Selection and Special Problems (K Kario and H Rakugi, Section Editors)

Abstract

It is now widely accepted that the angiotensin AT2 receptor (AT2R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT2R agonist C21 accelerated our understanding of AT2R-mediated protective signaling and actions. This article reviews the impact of C21 on blood pressure in normotensive and hypertensive animal models. Although C21 does not act as a classical antihypertensive drug, it could be useful in preventing hypertension-induced vascular and other end organ damages via anti-apoptotic, anti-fibrotic and anti-inflammatory actions. In particular, a strong body of evidence started to emerge around its anti-inflammatory feature. This property should be further investigated for potential clinical indications in cardiovascular diseases and beyond.

Keywords

Hypertension Blood pressure Angiotensin AT2Renin-angiotensin system RAS Compound 21 C21 Inflammation Antihypertensive drug therapy 

Introduction

The renin angiotensin system (RAS) plays a key role in blood pressure regulation. Its actions have been described as mostly dependent on stimulation of the Ang II receptor type 1 (AT1R). The development of AT1R blockers (ARB) and other receptor subtype-specific ligands in the 1990s revealed a second Ang II receptor subtype, the angiotensin AT2 receptor (AT2R) [1]. Since this discovery, several research groups have contributed to improving our understanding of this ‘enigmatic’ receptor [2]. It is now widely recognized that the AT2R receptor exerts actions opposing those of the AT1R, such as vasodilation, anti-proliferation, cell differentiation and anti-inflammation [3, 4, 5, 6, 7]. Although all mechanisms are still not fully deciphered, a picture of AT2R signaling has emerged with three major transduction mechanisms: (1) activation of the NO/cGMP pathway, (2) activation of a series of protein phosphatases and (3) activation of phospholipase A2 inducing the release of arachidonic acid [8]. All or some of these signaling cascades seem to be initiated by various proteins binding to the C-terminal end of the AT2-R such as the “AT2-R binding proteins” (ATIP or ATBP, [9, 10•]), the homeodomain enhancer protein and Zfhep, and the transcription factor PLZF (promyelocytic leukemia zinc finger, [11, 12]). These pathways have to be further investigated, especially with regard to their importance in anti- or pro-proliferative and cellular differentiation actions of the AT2R (see [6, 13•] for review of AT2R signaling).

The AT1R-opposed actions of the AT2R are not only determined by specific signaling pathways but also by the levels of AT2R expression in a given tissue. Early evidence for this was provided by Gohlke et al. in 1998 [14] and Pees et al. [15]. These authors demonstrated that AT2R stimulation in the aorta of adult SHR-SP was responsible for activation of the bradykinin/NO/GMPc pathway [14]. In contrast, they did not find any evidence for such AT2R-mediated NO production in the vascular wall of WKY rats [15]. What seems to be a discordance between these two rat strains can indeed be explained by a significantly higher expression level of AT2R in SHR compared to WKY [16]. In fact, the AT1R/AT2R ratio seems to be modified according to a given pathophysiologic state [17, 18]. In particular, AT2R expression is upregulated in tissue injury [19, 20], suggesting this could constitute a protective system during pathophysiologic processes.

In this context, exploiting the therapeutic potential of the ‘protective arm’ of the RAS, to which the AT2R as well as ACE2 and the Ang1-7/Mas receptor system belong [21], became a focus of interest with respect to drug development. The AT2R thus became a potential therapeutic target, and synthesis of compounds stimulating the AT2R was initiated. Compound 21 (C21) evolved from these efforts as the first selective nonpeptide AT2R agonist [22].

Before the advent of C21, research on AT2R functions was conducted either via indirect stimulation with Ang II in the presence of an ARB, via blockade of AT2R function with an AT2R antagonist or by elimination of AT2R function using AT2R knockout animals. The only early compound to directly stimulate the AT2R was the peptide CGP42112A. Unfortunately, due to its peptidic nature, its use in vivo was limited. Moreover, CGP42112A also features antagonistic properties at low concentrations [4]. The synthetic AT2R agonist, C21, thus constitutes the first pharmacokinetically unproblematic tool for the direct study of AT2R functions and the first AT2R agonist with drug-like properties. As a result, several experimental studies using C21 have been performed. With the background provided by preclinical studies since 2004 [22] and a currently ongoing toxicological program, it is anticipated that C21 is soon going to enter a clinical phase I study. In this article, we will summarize the important properties of C21 identified up to now.

Compound 21 and Blood Pressure

Since stimulation of AT2R induces vasodilation in isolated vessels and production of NO, one might reasonably think that administration of C21 would generate a decrease in blood pressure (BP). However, as summarized in Table 1, stimulation of AT2R in vivo does not yield a hypotensive effect – at least not acutely.
Table 1

Effect of C21 on blood pressure. Effect of C21 alone, associated with a high antihypertensive dose or a low non-antihypertensive dose of angiotensin receptor blocker (ARB) on blood pressure of normotensive, hypertensive or other pathologic animal models. C21 dosage, route and treatment duration are detailed

Animal model

C21 dosage

Route

Duration

Anesthetized animal

Effect on BP

Ref.

C21 alone

  S-D

0.05  mg/kg

i.v.

acute

Yes

No

[22]

  SHR

0.05  mg/kg

i.v.

acute

Yes

[22]

  WKY or SHR, 16-18 w.o.

50 to 1000  ng/kg/min

i.v.

4  h

No

No

[23••]

  S-D, 11-12 w.o.

100 to 300  ng/kg/min

i.v.

acute

Yes

No

[24]

  S-D, 2K1C

0.3  mg/kg/day

i.p.

4  days

No

No

[26•]

  Wistar rats with myocardial infarction

0.01, 0.03, or 0.3  mg/kg

i.p.

6  days

Yes

No

[33••]

  C57BL/6 mice, 10-12 w.o.

1, 3, and 10  mg/kg/day

i.p.

2  weeks

No

No

[25]

  SHR-SP, 6 w.o.

1  mg/kg/day

per os

6  weeks

No

No

[27•]

  Wistar, 10 w.o. + L-NAME

0.3  mg/kg/day

per os

6  weeks

No

No

[28•]

  SHR-SP, 4-5 w.o. + 1  % NaCl

0.75, 5 or 10  mg/kg/day

per os

until death

No

No

[29]

C21 associated with a high-dose ARB

  SHR-SP, 6 w.o. + losartan (10  mg/kg/day per os)

1  mg/kg/day

per os

6  weeks

No

No

[27•]

  Wistar, 10 w.o. + L-NAME + olmesartan medoxomil (10  mg/kg/day per os)

0.3  mg/kg/day

per os

6  weeks

No

No

[28•]

C21 associated with a low-dose ARB

  SHR, 16-18 w.o. + candesartan (0.1  mg/kg bolus i.v.)

50  ng/kg/min

i.v.

4  h

No

[23••]

In fact, C21 alone did not decrease blood pressure when administered in normotensive animals [22, 23••, 24, 25]. Moreover, in animal models of hypertension, regardless of the type of hypertension (genetic or induced), C21 did not provide any antihypertensive action either [23••, 26•, 27•, 28•, 29]. A decrease in BP was only described in the original publication about C21 synthesis and design [22]. In this study, a decrease in BP was observed following an acute i.v. infusion of C21 in SHR, but this was observed in anesthetized animals in which anesthesia may have hampered baroreflex control of BP. Thus, current evidence does not reveal any acute antihypertensive action of C21 in conscious animals, despite the diversity of treatment dosage, duration and route of administration tested (Table 1).

However, a potential antihypertensive effect of C21 alone may not be easily detectable in vivo because of a predominant AT1R-dependent angiotensinergic tone. Thus, in order to observe effects resulting from AT2R stimulation, it may be necessary to block AT1R. In fact, when combined with a low-dose ARB that does not modify BP, C21 exerted an antihypertensive action [23••]. This is in agreement with previous results obtained with CGP42112A [30, 31, 32]. When C21 was combined with a high dose of an ARB, which induces an antihypertensive effect, no additive effect of C21 on BP was observed [27•, 28•].

Although stimulation of AT2R with the AT2 agonist C21 does not engender direct, acute antihypertensive effects, a secondary reduction of BP may occur because of favorable effects of chronic C21 administration on vascular remodeling and kidney function. A trend towards a reduction of BP has indeed been observed in models of renal hypertension [26•], L-NAME induced hypertension [28•] and diabetic SHR-SP (unpublished observation), but these effects did not reach statistical significance.

Since the decrease in BP by AT2R-stimulation is only minor or in some studies not detectable at all, favorable effects of C21 in models of hypertensive end organ damage can be regarded as mainly or entirely BP independent. For example, Rehman et al. highlighted a reduction in vascular stiffness by C21 treatment in the aorta but also in mesenteric resistance arteries from hypertensive rats (SHR-SP) independently of any BP reduction [27•]. Moreover, our group has recently demonstrated that C21 treatment prevents the development of hypertension-induced aortic remodeling and accelerated pulse-wave velocity in L-NAME hypertensive rats without significantly changing BP [28•]. The C21-induced reduction of stiffness of mesenteric resistance arteries observed in the study by Rehman et al. as well as attenuated aortic stiffness in our study could in both cases be explained by a decrease in extracellular matrix components, collagen content and fibronectin. This may limit the increase in vascular resistance and, subsequently, the progression of hypertension as well as end-organ damage concomitant with chronic hypertension. Furthermore, at the kidney level, AT2R stimulation with C21 produced vasodilatory and natriuretic effects and may therefore also improve renal function [24]. Despite the absence of direct antihypertensive action, C21 could thus be a useful additional tool in the long-term management of hypertension.

Compound 21 and Anti-inflammation

Recent investigations, reviewed in the following, have revealed other beneficial effects beyond those for hypertension provided by C21.

In a model of myocardial infarction (MI) performed in Wistar rats, treatment with C21 improved cardiac function and decreased scar size after 7 days of treatment [33••]. The underlying mechanisms may include the strong anti-inflammatory effects of C21. Several inflammatory markers, increased following MI, were indeed lowered by C21, such as plasma monocyte chemoattractant protein-1 (MCP-1) and several proinflammatory cytokines. Moreover, in the peri-infarct zone, C21 attenuated the rise of apoptosis markers. These effects were blocked by the AT2R antagonist PD123319, supporting that specific AT2R stimulation by C21 exerted anti-inflammatory and anti-apoptotic actions in the context of MI.

In contrast, in a recent study with MI induced in mice, the authors did not observe a reduction of left ventricular remodeling following AT2R stimulation with C21 [34]. A potential reason for the lack of benefit of C21 in this study was the fact that the same dose of C21 used successfully as a bolus injection in a MI model in rats [33••] was applied in this study as a continuous infusion by minipumps, thus−considering a plasma half-life of C21 of 4 h−presumably not reaching effective plasma levels. Moreover, the authors themselves discussed that the larger infarct sizes obtained in their study could have masked beneficial effects of C21.

In a model of hypertension-induced renal dysfunction (salt-loaded SHR-SP), C21 delayed the occurrence of brain damage and reduced proteinuria [29]. These beneficial effects were specifically related to AT2R stimulation since they were abolished by PD123319. The authors observed an attenuation of inflammatory and fibrotic processes in the kidneys, pointing again to the anti-inflammatory properties of C21. In a two-kidney-one-clip (2K1C) rat model of hypertension, in which the inflammatory status is upregulated as highlighted by the increase of TNF-α tumor necrosis factor-α), IL-6 (interleukin 6) and TGF-β1 expression in the clipped kidneys, C21 significantly decreased these inflammatory markers [26•]. However, these effects were not completely blocked by PD123319. One possible explanation may rely on differences between these two AT2R ligands concerning the choice of their administration route or their affinity for AT2R [26•].

These recent studies highlighted that C21 affords anti-inflammatory properties via direct stimulation of AT2R. Underlying mechanisms were investigated by Rompe et al. [35••]. Human primary dermal fibroblasts were incubated with TNF-α in order to induce IL-6 expression. C21 treatment decreased IL-6, MCP-1 and TNF-α expressions, thus arguing for its anti-inflammatory action. This effect was also reported in endothelial cells from the human umbilical vein. Pre-incubation of cells with PD123319 abolished this effect, providing the evidence that these actions were AT2R-dependent. The authors further observed that the inhibitory effect of C21 on IL-6 expression was suppressed under inhibition of serine/threonine or tyrosine phosphatases, thus demonstrating that the anti-inflammatory cascade below AT2R stimulation implies stimulation of phosphatases. Moreover, the effect of C21 on IL-6 generation was also suppressed when cells were preincubated with a selective inhibitor of arachidonate epoxygenation, indicating that the arachidonic acid metabolite 11,12- epoxyeicosatrienoic acid (EET) constitutes a second messenger in the AT2R-dependent anti-inflammation pathway. This is in agreement with EET acting as an anti-inflammatory mediator in vascular inflammation [36]. Rompe et al. also investigated whether the changes in IL-6 expression by C21 were related to a change in NF-κB (nuclear factor-κB) activity as IL-6 transcription is under the control of this transcription factor. This was achieved by monitoring nuclear translocation of the NF-κB p50 subunit and also by measuring NF-κB–dependent IL-6 promoter transcriptional activity via a luciferase reporter assay. C21 indeed reduced NF-κB activity and translocation. Moreover, in a mouse model of cutaneous inflammation, in which IL-6, MCP-1 and TNF-α mRNA are upregulated, C21 induced a significant reduction of these inflammatory markers, providing further in vivo evidence of C21’s anti-inflammatory properties. Thus, AT2R-dependent anti-inflammation seems to involve activation of protein phosphatases, epoxidation of arachidonic acid to EETs and inhibition of NF-κB reducing pro-inflammatory cytokines (Fig. 1) [35••]. It is important to note that, on the IL-6 promoter level, the NF-κB inhibition in this study was comparable in strength to inhibition provided by hydrocortisone, thus supporting the idea that C21 should be studied as a potential drug candidate in inflammatory diseases [35••].
Fig. 1

Schematic overview of the AT2R-dependent anti-inflammation signaling pathway, counteracting the proinflammatory action of AT1R activation. Due to its anti-inflammatory properties, the AT2R agonist C21 may be the ideal partner of ARBs in the context of hypertension and related cardiovascular complications. C21 could also enlarge its therapeutic perspectives to non-cardiovascular inflammatory diseases. Ang II, angiotensin II; AT1R, angiotensin II receptor subtype 1; AT2R, angiotensin II receptor subtype 2; ARB, angiotensin receptor blocker; C21, compound 21; CYP, cytochrome P450; AA, arachidonic acid; 11, 12-EET, 11, 12-epoxyeicosatrienoic acid; NF-kB, nuclear factor κB

Finally, as inflammatory processes also contribute to the pathophysiology of hypertension, their inhibition may potentiate the benefit of blood pressure reduction [37]. The AT2R agonist C21, partly via its anti-inflammatory properties, may thus be the ideal partner of ARBs in the context of hypertension and related cardiovascular complications (Fig. 1).

Perspectives

Although stimulation of AT2R by C21 seems to generate numerous actions such as anti-apoptosis and anti-fibrosis [33••], several recent studies reviewed above highlight anti-inflammation as a major function of C21. Therapeutically, C21 could therefore be used as a tool in order to counteract pathologic inflammatory processes. Beyond cardiovascular diseases, in which inflammation is only a part of the pathophysiological process, C21 could enlarge its therapeutic perspectives to non-cardiovascular inflammatory diseases.

Beyond classical treatments, stem cells constitute promising candidates for future therapies [38]. Moreover, there is a growing body of evidence suggesting that RAS, and AT2R in particular, are implied in the proliferation and differentiation of hematopoietic and mesenchymal stem cells (see [39•] for review). In their recent review, Durik et al. addressed the impact of RAS modulation, and in particular AT2R stimulation, on tissue regeneration by progenitor cells [39•]. Indirect evidence suggests that AT2R stimulation may improve the therapeutic effects of MSC grafts in myocardial infarction [40] and brain ischemia [41].

The cellular mechanisms involved in the cardioprotective role of AT2R have been further investigated following MI. The expression of AT2R has been indeed observed in human cardiac stem cells as well as in CD8-positive T cells (CD8+ AT2R+ T cells) in the peri-infarct area [42••, 43]. AT2Rs are increased in human cardiac stem cells after MI, and their stimulation with C21 attenuated apoptosis of cardiomyocytes [43]. Besides, AT2Rs are also expressed in a fraction of CD8-positive T cells in the peri-infarct area [42••]. Contrary to CD8+ AT2R- T cells, CD8+ AT2R+ T cells did not induce cytotoxicity to cardiomyocytes and exhibited a decreased expression of proinflammatory cytokines. Intramyocardial transplantation of these cells after MI reduced the infarct size, thus providing in vivo evidence of cardioprotection via CD8+ AT2R+ T cells. These studies highlighted an AT2R-mediated cellular mechanism protecting the heart from injury at least in part via anti-apoptotic and anti-inflammatory actions. This could contribute to the beneficial effects observed in post-MI following an acute [33••] or a chronic C21 treatment [44].

Otherwise, the neuroprotective action of AT2R has in particular been previously investigated after transient cerebral ischemia by unilateral middle cerebral artery occlusion in the rat [19]. In this model, AT2Rs were upregulated in neuronal cells of the peri-ischemic area, and this was associated with cerebroprotective actions. In order to explore the underlying mechanisms, the authors focused on the role of AT2Rs in primary neuronal cells. They highlighted that AT2R stimulation promotes neurite outgrowth and neuronal survival [19]. This may support the AT2R-dependent neuroprotection provided by MSC grafts during brain ischemia [41]. Stimulation of AT2R of progenitor cells seems to improve the effects of cell therapy treatments in the context of cardiovascular and neural injury, acting as a repair system [39•].

Conclusion

Although the AT2R agonist C21 does not act as a classical antihypertensive drug, it could be useful in preventing hypertension-induced organ damage. Moreover, a body of evidence emerges around its anti-inflammatory feature: this should be further investigated for a potential clinical indication.

Considering the AT2R expression levels in healthy (low expression) and injured tissues (upregulated expression), direct AT2R stimulation with C21 could constitute a selective repair therapy directed at the injury site, with a limited occurrence of adverse events. AT2R agonists are the first agonists of the RAS developed with a therapeutic goal. Up to now, the therapeutic goal of interfering with the RAS was slowing down the renin/ACE/AT1 axis. In contrast to this approach, AT2R agonists, with the lead compound C21, may afford new therapeutic options via promotion of the “protective RAS.”

Notes

Disclosure

S. Foulquier: none; U. M. Steckelings: grant and support for travel to meetings for the study or other purposes from Vicore Pharma; T. Unger: stock/stock options from Vicore Pharma.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance

  1. 1.
    Chiu AT, Herblin WF, McCall DE, et al. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;165:196–203.PubMedCrossRefGoogle Scholar
  2. 2.
    Unger T. The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens. 1999;17:1775–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Vincent J-M, Kwan YW, Chan SL, et al. Constrictor and dilator effects of angiotensin II on cerebral arterioles. Stroke. 2005;36:2691–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Stoll M, Steckelings UM, Paul M, et al. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Meffert S, Stoll M, Steckelings UM, et al. The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol. 1996;122:59–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Steckelings UM, Kaschina E, Unger T. The AT2 receptor–a matter of love and hate. Peptides. 2005;26:1401–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Wu L, Iwai M, Li Z, et al. Regulation of inhibitory protein-κB and monocyte chemoattractant protein-1 by angiotensin II type 2 receptor activated Src homology protein tyrosine phosphatase-1 in fetal vascular smooth muscle cells. Mol Endocrinol. 2004;18:666–78.PubMedCrossRefGoogle Scholar
  8. 8.
    Nouet S, Nahmias C. Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab. 2000;11:1–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Wruck CJ, Funke-Kaiser H, Pufe T, et al. Regulation of transport of the angiotensin AT2 receptor by a novel membrane-associated Golgi protein. Arterioscler Thromb Vasc Biol. 2005;25:57–64.PubMedGoogle Scholar
  10. 10.
    • Rodrigues-Ferreira S, Nahmias C: An ATIPical family of angiotensin II AT2 receptor-interacting proteins. Trends Endocrinol Metab. 2010, 21: 684–690. This article reviews recent discoveries concerning a family of AT 2 receptor-interacting proteins involved in the AT 2 R signaling, regulation and function.PubMedCrossRefGoogle Scholar
  11. 11.
    Stoll M, Hahn AWA, Jonas U, et al. Identification of a zinc finger homoeodomain enhancer protein after AT(2) receptor stimulation by differential mRNA display. Arterioscler Thromb Vasc Biol. 2002;22:231–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Senbonmatsu T, Saito T, Landon EJ, et al. A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy. EMBO J. 2003;22:6471–82.PubMedCrossRefGoogle Scholar
  13. 13.
    • Funke-Kaiser H, Reinemund J, Steckelings UM, Unger T: Adapter proteins and promoter regulation of the angiotensin AT2 receptor--implications for cardiac pathophysiology. J Renin Angiotensin Aldosterone Syst 2010, 11: 7–17. This article reviews new identified pathways implied in the modulation of signaling, expression and function of AT 2 R, especially via AT 2 R adapter proteins and heterodimer formation.PubMedCrossRefGoogle Scholar
  14. 14.
    Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension. 1998;31:349–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Pees C, Unger T, Gohlke P. Effect of angiotensin AT2 receptor stimulation on vascular cyclic GMP production in normotensive Wistar Kyoto rats. Int J Biochem Cell Biol. 2003;35:963–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Touyz RM, Endemann D, He G, et al. Role of AT2 receptors in angiotensin II-stimulated contraction of small mesenteric arteries in young SHR. Hypertension. 1999;33:366–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Widdop RE, Vinh A, Henrion D, Jones ES. Vascular angiotensin AT2 receptors in hypertension and ageing. Clin Exp Pharmacol Physiol. 2008;35:386–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Foulquier S, Dupuis F, Perrin-Sarrado C, et al. High salt intake abolishes AT2-mediated vasodilation of pial arterioles in rats. J Hypertens. 2011;29:1392–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Li J, Culman J, Hörtnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J. 2005;19:617–9.PubMedGoogle Scholar
  20. 20.
    Makino I, Shibata K, Ohgami Y, et al. Transient upregulation of the AT2 receptor mRNA level after global ischemia in the rat brain. Neuropeptides. 1996;30:596–601.PubMedCrossRefGoogle Scholar
  21. 21.
    Steckelings UM, Paulis L, Unger T, Bader M. Emerging drugs which target the renin-angiotensin-aldosterone system. Expert Opin Emerg Drugs. 2011;16:619–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Wan Y, Wallinder C, Plouffe B, et al. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. J Med Chem. 2004;47:5995–6008.PubMedCrossRefGoogle Scholar
  23. 23.
    •• Bosnyak S, Welungoda IK, Hallberg A, et al.: Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. Br. J. Pharmacol. 2010, 159: 709–716. This is the first study demonstrating a C21-induced vasorelaxation in vitro that is translated into a vasodepressor response in vivo when combined with a low dose of AT 1 R blocker.PubMedCrossRefGoogle Scholar
  24. 24.
    Hilliard LM, Jones ES, Steckelings UM, et al. Sex-specific influence of angiotensin type 2 receptor stimulation on renal function: a novel therapeutic target for hypertension. Hypertension. 2012;59:409–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Jing F, Mogi M, Sakata A, et al. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory. J Cereb Blood Flow Metab. 2012;32:248–55.PubMedCrossRefGoogle Scholar
  26. 26.
    • Matavelli LC, Huang J, Siragy HM: Angiotensin AT2 receptor stimulation inhibits early renal inflammation in renovascular hypertension. Hypertension 2011, 57: 308–313. This study provides evidence for the anti-inflammatory actions of C21 in clipped kidney of the Goldblatt hypertension model.PubMedCrossRefGoogle Scholar
  27. 27.
    • Rehman A, Leibowitz A, Yamamoto N, et al.: Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats. Hypertension 2012, 59: 291-299. This is the first study reporting effects of chronic C21 treatment on the vascular wall in genetic hypertensive rats. C21 reduced the stiffness of mesenteric resistance arteries independently of any blood pressure reduction.PubMedCrossRefGoogle Scholar
  28. 28.
    • Paulis L, Becker STR, Lucht K, et al.: Direct angiotensin II type 2 receptor stimulation in Nω-nitro-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling. Hypertension 2012, 59: 485–492. This is the first study reporting the effects of chronic C21 treatment on the vascular wall in a hypertension-induced model. C21 prevented aortic stiffening independently of any blood pressure reduction.PubMedCrossRefGoogle Scholar
  29. 29.
    Gelosa P, Pignieri A, Fändriks L, et al. Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage. J Hypertens. 2009;27:2444–51.PubMedCrossRefGoogle Scholar
  30. 30.
    Li XC, Widdop RE. AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in conscious SHR. Br J Pharmacol. 2004;142:821–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Barber MN, Sampey DB, Widdop RE. AT(2) receptor stimulation enhances antihypertensive effect of AT(1) receptor antagonist in hypertensive rats. Hypertension. 1999;34:1112–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Carey RM, Howell NL, Jin XH, Siragy HM. Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats. Hypertension. 2001;38:1272–7.PubMedCrossRefGoogle Scholar
  33. 33.
    •• Kaschina E, Grzesiak A, Li J, et al.: Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation 2008, 118: 2523–2532. This is the first in vivo study using C21. A short treatment with C21 improved cardiac function and decreased scar size after myocardial infarction. This was observed in association with a decrease in inflammation and apoptosis markers.PubMedCrossRefGoogle Scholar
  34. 34.
    Jehle AB, Xu Y, Dimaria JM, et al. A nonpeptide angiotensin II type 2 receptor agonist does not attenuate postmyocardial infarction left ventricular remodeling in mice. J Cardiovasc Pharmacol. 2012;59:363–8.PubMedCrossRefGoogle Scholar
  35. 35.
    •• Rompe F, Artuc M, Hallberg A, et al.: Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. Hypertension 2010, 55: 924–931. This is the first study showing anti-inflammatory effects of direct AT 2 R stimulation by C21 in vitro and in vivo. Underlying signaling mechanisms are reported.PubMedCrossRefGoogle Scholar
  36. 36.
    Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999;285:1276–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Savoia C, Schiffrin EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens. 2006;15:152–8.PubMedGoogle Scholar
  38. 38.
    Sánchez PL, Villa A, Sanz R, et al. Present and future of stem cells for cardiovascular therapy. Ann Med. 2007;39:412–27.PubMedCrossRefGoogle Scholar
  39. 39.
    • Durik M, Sevá Pessôa B, Roks AJM: The renin-angiotensin system, bone marrow and progenitor cells. Clin. Sci. 2012, 123: 205–223. This review addresses the impact of renin-angiotensin-system modulation on tissue regeneration by progenitor cells. In particular, they highlight the potential importance of AT 2 R stimulation with agonists in the future of stem cell therapy.PubMedCrossRefGoogle Scholar
  40. 40.
    Numasawa Y, Kimura T, Miyoshi S, et al. Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis. Stem Cells. 2011;29:1405–14.PubMedGoogle Scholar
  41. 41.
    Iwanami J, Mogi M, Li J-M, et al. Deletion of angiotensin II type 2 receptor attenuates protective effects of bone marrow stromal cell treatment on ischemia-reperfusion brain injury in mice. Stroke. 2008;39:2554–9.PubMedCrossRefGoogle Scholar
  42. 42.
    •• Curato C, Slavic S, Dong J, et al.: Identification of noncytotoxic and IL-10-producing CD8 + AT2R + T cell population in response to ischemic heart injury. J. Immunol. 2010, 185: 6286–6293. This study revealed the expression of AT 2 R in CD8 + T cells in the peri-infarct myocardium, thus revealing an AT 2 R-mediated cellular mechanism in regulating immune response during ischemic heart injury.PubMedCrossRefGoogle Scholar
  43. 43.
    Altarche-Xifró W, Curato C, Kaschina E, et al. Cardiac c-kit + AT2+ cell population is increased in response to ischemic injury and supports cardiomyocyte performance. Stem Cells. 2009;27:2488–97.PubMedCrossRefGoogle Scholar
  44. 44.
    Lauer D, Slavic S, Sommerfeld M, et al. AT2 receptor stimulation improves cardiac function 6 weeks after myocardial infarction in the rat. [Abstract ESH 8 C.03] Presented at the 22nd European Meeting on Hypertension and Cardiovascular Prevention. London, Great Britain, April 26-29, 2012.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Sébastien Foulquier
    • 1
    • 3
  • U. Muscha Steckelings
    • 2
  • Thomas Unger
    • 1
    • 3
  1. 1.Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
  2. 2.Center for Cardiovascular ResearchCharité -Universitätsmedizin BerlinBerlinGermany
  3. 3.CARIM - School for Cardiovascular DiseasesMaastricht UniversityMaastrichtThe Netherlands

Personalised recommendations