| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Introduction |
1 Department of Physiology and Functional Genomics, University of Florida, College of Medicine, Gainesville, FL, USA 2 Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, University of Bristol, Bristol, Avon, UK
This issue is dedicated to the discussion of recent advances in the field of the renin–angiotensin system (RAS). It contains review articles and peer-reviewed original papers on the two newest members of the system: angiotensin-converting enzyme 2 (ACE2) and (pro)renin receptor (PRR). This issue provides an up-to-date discussion on their involvement in cardiovascular disease (CVD).
It is well established that the RAS plays a critical role in the control of cardiovascular homeostasis, and its hyperactivity leads to many devastating effects in the cardiovascular system, including hypertension, heart disease, coronary heart disease, cerebral vascular disease, atherosclerosis, stroke, renal disease and metabolic syndrome. This conclusion is further strengthened by the fact that the pharmacotherapy targeting the RAS is one of the most successful strategies for the treatment and control of these diseases. Despite the success of drugs that block RAS activity, the prevalence of CVD has been increasing steadily in the last several decades. This has led many scientists to conclude that new approaches and drug targets must be discovered in order to develop more effective therapeutics for both better control and eventual cure of CVD. In this regard, the discovery of ACE2 and PRR are extremely relevant because they provide novel targets for CVD therapeutics.
Angiotensin-converting enzyme 2 was discovered in 2000 as an ACE homologue and is a key player in the conversion of angiotensin II (Ang II) to angiotensin(1–7) [Ang(1–7)]. Thus, levels of ACE2 in the cardiovascular system are critical in balancing the vasoconstrictive, proliferative and hypertrophic effects of the angiotensin-converting enzyme (ACE)–Ang II–angiotenisin II type 1 receptor (AT1R) axis with the vasodilatatory, antiproliferative actions of ACE2–Ang(1–7)–Mas axis. The review article by Santos et al. (2008) summarizes our latest understanding of the ACE2–Ang(1–7)–Mas axis and its role in pathophysiology of the cardiovascular system. Reviews by Alenina et al. (2008) and Gurley & Coffman (2008) describe the usefulness and limitations of the use of genetically altered animal models of ACE2, Ang(1–7) and Mas for investigations into blood pressure control. In addition, the implications of ACE2 in renal pathophysiology are discussed by Soler et al. (2008). Imai et al. (2008) summarize their exciting observations on the involvement of ACE2 in acute lung injury.
Seven research papers present evidence for the role of the ACE2–Ang(1–7)–Mas axis in cardiac/vascular physiology and pathophysiology. For example, the study of Zulli et al. (2008) demonstrates the presence of ACE2 in atherosclerotic plaques and co-localization with CD34 cells, while Guy et al. (2008) describe its presence in human cardiac myofibroblasts. The study of Garabelli et al. (2008) demonstrates that ACE2 is the primary pathway in the conversion of Ang II to Ang(1–7). Importance of the interplay between Ang II and Ang(1–7) in the regulation of matrix metalloproteases (MMPs) in human cardiocytes is presented in the paper by Pan et al. (2008). This study is significant in view of the role of MMPs in cardiac hypertrophy and heart failure. Giani et al. (2008) provide evidence that the antiproliferative effect of Ang(1–7) in the heart could be mediated by inhibition of Ang II-induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) signalling. Burchill et al. (2008) demonstrate increased ACE2 expression in acute kidney injury and Filho et al. (2008) show a selective increase in Ang(1–7) and its receptor in the spontaneously hypertensive rat (SHR) heart following physical training. Research papers describing the role of ACE2 and Ang(1–7) in the kidney for regulation of body fluid homeostasis are presented. For example, Ji et al. (2008) present data on the involvement of ACE2 in hypertension; Brosnihan et al. (2008) demonstrate the regulation of ACE2 by oestrogen and Lara et al. (2008) present evidence of a cross-talk between Ang II and Ang(1–7). Involvement of ACE2 in brain regions controlling the cardiovascular system is discussed by Elased et al. (2008), Diz et al. (2008) and Lin et al. (2008). Finally, Lew et al. (2008) present evidence for the existence of a possible inhibitor of ACE2 in human plasma, a finding that may have important implications clinically.
Discovery of a specific receptor for renin and its precursor, prorenin, in 2002 has revolutionized the field of the RAS. Accumulating evidence supports the hypothesis that the (pro)renin receptor (PRR) has duel functions: (i) Ang II-independent actions involving intracellular signalling that triggers expression of profibrotic genes; and (ii) Ang II-dependent actions involving increased catalytic activity of the PRR-bound prorenin. Discovery of this receptor takes on an added importance in view of the clinical use of renin inhibitors as a new class of antihypertensives, which are known to increase both renin and prorenin levels. Nguyen & Danser (2008) bring us up to date on this subject in their exciting review. In addition, Siragy & Huang (2008) present important evidence for the presence of PRR in the kidney and its altered expression in diabetes. Finally, Shan et al. (2008) demonstrate that the PRR is expressed in central neurons and regulates neuronal activity. This observation may have major implications in defining the role of the brain RAS in neurogenic hypertension.
We hope that this issue of Experimental Physiology is helpful to both basic and clinical researchers in providing a state-of-the-art presentation of this fast-emerging field of ACE2 and PRR and their implications in cardiovascular physiology and pathophysiology.
References
Alenina N, Xu P, Rentzsch B, Patkin EL & Bader M (2008). Genetically altered animal models for Mas and angiotensin-(1–7). Exp Physiol 93, 528–537.
Brosnihan KB, Hodgin JB, Smithies O, Maeda N & Gallagher P (2008). Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-
knock-out mice. Exp Physiol 93, 658–664.
Burchill L, Velkoska E, Dean RG, Lew RA, Smith AI, Levidiotis V & Burrell LM (2008). Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression. Exp Physiol 93, 622–630.
Diz DI, Garcia-Espinosa MA, Gegick S, Tommasi EN, Ferrario CM, Tallant EA, Chappell MC & Gallagher PE (2008). Injections of angiotensin-converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats. Exp Physiol 93, 694–700.
Elased KM, Cunha TS, Marcondes FK & Morris M (2008). Brain angiotensin-converting enzymes: role of angiotensin-converting enzyme 2 in processing angiotensin II in mice. Exp Physiol 93, 665–674.
Filho AG, Ferreira AJ, Santos SHS, Neves SRS, Silva Camargos ER, Becker LK, Belchior HA, Dias-Peixoto MF, Pinheiro SVB & Santos RAS (2008). Selective increase of angiotensin(1–7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training. Exp Physiol 93, 589–598.
Garabelli P, Modrall JG, Penninger JM, Ferrario CM & Chappell MC (2008). Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart. Exp Physiol 93, 613–621.
Giani JF, Gironacci MM, Muñoz MC, Turyn D & Dominici FP (2008). Angiotensin-(1–7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity. Exp Physiol 93, 570–578.
Gurley SB & Coffman TM (2008). Angiotensin-converting enzyme 2 gene targeting studies in mice: mixed messages. Exp Physiol 93, 538–542.
Guy L, Lambert DW, Turner AJ & Porter KE (2008). Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts. Exp Physiol 93, 579–588.
Hamming I, van Goor H, Turner AJ, Rushworth CA, Michaud AA, Corvol P & Navis G (2008). Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats. Exp Physiol 93, 631–638.
Imai Y, Kuba K & Penninger JM (2008). The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury. Exp Physiol 93, 543–548.
Ji H, Menini S, Zheng W, Pesce C, Wu X & Sandberg K (2008). Role of angiotensin-converting enzyme 2 and angiotensin(1–7) in 17β-oestradiol regulation of renal pathology in renal wrap hypertension in rats. Exp Physiol 93, 648–657.
Lara LS, Correa JS, Lavelle AB, Lopes AG & Caruso-Neves Celso (2008). The angiotensin receptor type 1–Gq protein–phosphatidyl inositol phospholipase Cβ–protein kinase C pathway is involved in activation of proximal tubule Na+-ATPase activity by angiotensin(1–7) in pig kidneys. Exp Physiol 93, 639–647.
Lew RA, Warner FJ, Hanchapola I, Yarski MA, Manohar J, Burrell LM & Smith AI (2008). Angiotensin-converting enzyme 2 catalytic activity in human plasma is masked by an endogenous inhibitor. Exp Physiol 93, 685–693.
Lin Z, Chen Y, Zhang W, Chen AF, Lin S & Morris M (2008). RNA interference shows interactions between mouse brainstem angiotensin AT1 receptors and angiotensin-converting enzyme 2. Exp Physiol 93, 676–684.
Nguyen G & Danser AHJ (2008). Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models. Exp Physiol 93, 557–563.
Pan C-H, Wen C-H, Lin C-S (2008). Interplay of angiotensin II and angiotensin(1–7) in the regulation of matrix metalloproteinases of human cardiocytes. Exp Physiol 93, 599–612.
Santos RAS, Ferreira AJ & Simões e Silva AC (2008). Recent advances in the mammalian angiotensin-converting enzyme 2–angiotensin(1–7)–Mas axis. Exp Physiol 93, 519–527.
Shan Z, Cuadra AE, Sumners C & Raizada MK (2008). Characterization of a functional (pro)renin receptor in rat brain neurons. Exp Physiol 93, 701–708.
Siragy HM & Huang J (2008). Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp Physiol 93, 709–714.
Soler MJ, Wysocki J & Batlle D (2008). Angiotensin-converting enzyme 2 and the kidney. Exp Physiol 93, 549–556.
Zulli A, Rai S, Buxton BF, Burrell LM & Hare DL (2008). Co-localization of angiotensin-converting enzyme 2-, octomer-4- and CD34-positive cells in rabbit atherosclerotic plaques. Exp Physiol 93, 564–569.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
