doi: 10.1161/CIRCRESAHA.108.173781
© 2008 American Heart Association, Inc.
Editorials |
Angiotensin-Converting Enzyme 2
A New Player in Central Sympathetic Regulation?
From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
Correspondence to Irving H. Zucker, PhD, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail izucker{at}unmc.edu
See related article, pages 729–736
Key Words: adrenergic regulation • angiotensin II • ACE 2
There is a "new kid on the block" in the control of the renin-angiotensin system (RAS). The discovery of angiotensin (Ang)-converting enzyme (ACE)2, a catabolic enzyme, that cleaves the octapeptide, Ang II into a septapeptide, Ang-(1-7),1,2 has opened up new vistas in the way we think about the regulation and biological effects of Ang II. ACE 2 was originally discovered in yeast3 as a gene product that codes for a protein that is a homolog of the more widely known protease ACE. ACE2 cleaves the C-terminal amino acid from Ang II and other peptides. For many years, the work of Ferrario and Chappel4 provided evidence that Ang-(1-7) operated in the central nervous system, as well as in the peripheral circulation to produce effects that were, in general, opposite to that of Ang II. Recently, the discovery that Ang-(1-7) binds to a specific membrane receptor, the mas receptor,5–7 suggests that this metabolite may play a regulatory role in cell signaling and organ function. Clearly, the balance between the classic ACE and ACE2 will determine the physiological effect of activation of the RAS. Furthermore, the potential for therapeutic targeting of ACE2 and its role in the pathogenesis of various diseases such as hypertension and heart failure is intriguing.
To further understand the potential for ACE 2 in the brain to alter sympathetic function and drinking, 2 well-known effects of central Ang II, Feng et al, in this issue of Circulation Research,8 used adenoviral transfection techniques to overexpress ACE2 in the mouse brain. Overexpression was prominent in the subfornical organ (SFO), an area involved in sympathetic regulation and thirst in response to Ang II.9 This structure is heavily endowed with Ang type 1 receptors (AT1R). Because the SFO is devoid of a blood–brain barrier relative to the majority of the brain, it is well suited to "sense" both cerebrospinal fluid and circulating substances. Therefore, the SFO is an ideal structure to test the hypothesis that overexpression of ACE2 alters responses to Ang II. There are 2 striking results presented in this study. The first relates to the physiological responses to ACE2 overexpression when challenged by intracerebroventricular Ang II. Both the pressor and drinking responses were dramatically reduced in ACE2-transfected mice. The second and perhaps the most interesting result is that overexpression of ACE2 reduced AT1R expression in the SFO, as well as in isolated neuroblastoma cells.
Ang II signaling in most tissues is mediated by multiple pathways. The dominant pathway depends on tissue type and the function to be mediated. This is especially true in the central nervous system, where all of the components of the RAS exist. There is evidence that various components, such as angiotensinogen, may actually be predominant in glia,10 whereas others appear to predominate in neurons.11 A question that has been posed for many years is how the central RAS system is regulated. In fact, except for the kidney, this question is still valid for most tissues. Whatever the stimulus to activation of the central RAS (another fruitful area of investigation), there is growing evidence that augmented central Ang II activates a pathway that results in further upregulation of the AT1R12–14 and a decrease in the AT2R.15 This mechanism may be responsible for normal physiological regulatory processes to be transformed into a pathological process. For instance, in the setting of chronic heart failure, AT1R expression is upregulated in the rostral ventrolateral medulla14,16 and most likely in the paraventricular nucleus of the hypothalamus as well.17 This process is completely dependent on binding of Ang II to the AT1R14 and to activation of a transcriptional pathway that most likely involves multiple transcription factors and their phosphorylation (see Figure). This effect can be mimicked by Ang II infusion in animals and by incubation with Ang II in cells.14 The fact that Feng et al8 demonstrated a downregulation in AT1R expression in the SFO following central ACE2 adenoviral transfection raises the question as to the physiological and pathological significance of this process. Is this effect dependent on the generation of Ang-(1-7)? If so, does it involve the mas receptor and do any of the downstream signaling steps involve components of the pathway shown in the Figure? These are critical questions whose answers will depend on novel tissue and cell specific transgenic models and specific inhibitors of both ACE2 and the mas receptor.
|
Finally, the relationship between AT1 and AT2 receptor expression in the brain may be of importance in the regulation of this system. A reciprocal relationship appears to occur for expression of these 2 receptors.18,19 If expression of AT1 receptors influences AT2 expression, then the degree to which ACE2 is activated may play a determining role controlling the balance between these 2 receptors and their downstream signaling pathways. At this point, it is important to focus on how each of the components of the RAS is regulated in the brain to alter sympathetic neuronal function and ultimately peripheral vascular and cardiac function.
 |
Acknowledgments |
|---|
Sources of Funding
Some of the work by the author referenced in this editorial was funded by the National Heart, Lung, and Blood Institute grant PO1 HL62222.
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Chappell MC, Modrall JG, Diz DI, Ferrario CM. Novel aspects of the renal renin-angiotensin system: angiotensin-(1-7), ACE2 and blood pressure regulation. Contrib Nephrol. 2004; 143: 77–89.[Medline] [Order article via Infotrieve]
2. Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, Canver CC. Increased angiotensin-(1-7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation. 2003; 108: 1707–1712.
3. Butler G, Thiele DJ. ACE2, an activator of yeast metallothionein expression which is homologous to SWI5. Mol Cell Biol. 1991; 11: 476–485.
4. Chappel MC, Ferrario CM. ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1-7). Kidney Int. 2006; 70: 8–10.[CrossRef][Medline] [Order article via Infotrieve]
5. Hanley MR, Cheung WT, Hawkins P, Poyner D, Benton HP, Blair L, Jackson TR, Goedert M. The mas oncogene as a neural peptide receptor: expression, regulation and mechanism of action. Ciba Found Symp. 1990; 150: 23–38.[Medline] [Order article via Infotrieve]
6. Pinheiro SV, Simoes e Silva AC, Sampaio WO, de Paula RD, Mendes EP, Bontempo ED, Pesquero JB, Walther T, Alenina N, Bader M, Bleich M, Santos RA. Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004; 44: 490–496.
7. Tallant EA, Ferrario CM, Gallagher PE. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol. 2005; 289: H1560–H1566.
8. Feng Y, Yue X, Xia H, Bindom SM, Hickman PJ, Filipeanu CM, Wu G, Lazartigues E. 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: 729–736.
9. Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CD. Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest. 2007; 117: 1088–1095.[CrossRef][Medline] [Order article via Infotrieve]
10. Sakima A, Averill DB, Kasper SO, Jackson L, Ganten D, Ferrario CM, Gallagher PE, Diz DI. Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen. Am J Physiol Heart Circ Physiol. 2007; 292: H1412–H1419.
11. Lavoie JL, Cassell MD, Gross KW, Sigmund CD. Localization of renin expressing cells in the brain, by use of a REN-eGFP transgenic model. Physiol Genomics. 2004; 16: 240–246.
12. Chan SH, Wang LL, Tseng HL, Chan JY. Upregulation of AT1 receptor gene on activation of protein kinase Cbeta/nicotinamide adenine dinucleotide diphosphate oxidase/ERK1/2/c-fos signaling cascade mediates long-term pressor effect of angiotensin II in rostral ventrolateral medulla. J Hypertens. 2007; 25: 1845–1861.[CrossRef][Medline] [Order article via Infotrieve]
13. Gao L, Wang W, Li YL, Schultz HD, Liu DM, Cornish KG, Zucker IH. Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol. 2005; 288: H2271–H2279.
14. Liu D, Gao L, Roy SK, Cornish KG, Zucker IH. Neuronal AT1 receptor up-regulation in heart failure: activation of AP-1 and JNK. Circ Res. 2006; 99: 1004–1011.
15. Saito M, Shinohara Y, Sasaki H, Netsu Y, Yoshida M, Nakahata N. Type 1 angiotensin receptor (AT1-R)-mediated decrease in type 2 angiotensin receptor mRNA level is dependent on G(q) and extracellular signal-regulated kinase 1/2 in AT1-R-transfected PC12 cells. J Neuroendocrinol. 2008; 20: 299–308.[CrossRef][Medline] [Order article via Infotrieve]
16. Liu J-L, Irvine S, Reid IA, Patel KP, Zucker IH. Chronic exercise reduces sympathetic nerve activity in rabbits with pacing-induced heart failure: a role for angiotensin II. Circulation. 2000; 102: 1854–1862.
17. Zhu G-Q, Zucker IH, Wang W. Central AT1 receptors are involved in the enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure. Basic Res Cardiol. 2002; 97: 320–326.[CrossRef][Medline] [Order article via Infotrieve]
18. Gao L, Wang W, Wang W, Li H, Sumners C, Zucker IH. Effects of angiotensin type 2 receptor overexpression in the rostral ventrolateral medulla on blood pressure and urine excretion in normal rats. Hypertension. 2008; 51: 521–527.
19. Brosnihan KB, Hodgin JB, Smithies O, Maeda N, Gallagher P. Tissue specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by estrogen in ApoE/ERa knock-out mice. Exp Physiol. January 11, 2008 Epub ahead of print.
Related Article:
Circ. Res. 2008 102: 729-736.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||