Download Circulation Research Classics

Circulation Research Classics
To mark the 60th birthday of Circulation Research (1953–2013), the editors have commissioned Circulation Research Classics, a series of commentaries highlighting seminal articles published in the journal over the past 6 decades that have importantly shaped cardiovascular research.
Written by leading experts, Circulation Research Classics are intended to describe the impact of these articles on the field by putting them in a
historical perspective. The concept of classic is inextricably linked to time—a classic is something that maintains its value regardless of its age.
Thus, an important consideration in selecting the articles to be highlighted is that they have stood the test of time, which is the most reliable
indicator of the value of scientific work. By looking back at the illustrious past of Circulation Research, we hope to promote a deeper appreciation
of the contributions of this journal to the advancement of knowledge.
The Discovery of the ACE2 Gene
A.J. Marian
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A Novel Angiotensin-Converting Enzyme–Related
Carboxypeptidase (ACE2) Converts Angiotensin I to
Angiotensin 1–9
Donoghue et al
Circ Res. 2000;87:E1–E9.
Eureka moments but rather are based on a series of small discoveries that pave the path for the major breakthroughs. Thus,
contributions of all steps in the ladder of scientific discoveries,
whether small or large, are important. Nevertheless, certain
steps epitomize the breakthroughs and apt to Dr Koshland’s
Cha-Cha-Cha Theory of Scientific Discoveries. The progress
in cardiovascular science is no exception. Hence, the Editors
of Circulation Research have invited the audience to identify
and highlight seminal discoveries that have been published in
Circulation Research and have had or are expected to have
major impacts in the cardiovascular sciences.
The initiative is laudable and the task is not trivial. The
challenge is to recognize the big steps in the ladder of scientific discoveries. There is no predefined criterion that easily
lends itself to spotting the seminal discoveries. The inability
to identify the potential significance of the new findings is best
illustrated in the case of the discovery of DNA, which was first
isolated by Mieshner in 1869.3 For the next 75 years, it was
reasoned that DNA, a large monotonous macromolecule composed only of 4 repeating units, could not have much function
and that protein and not DNA was responsible for inheritance.
The classic work of Avery, MacLeod, and McCarty in 1944
and later Hershey and Chase in 1952 established DNA as the
molecule responsible for inheritance.4,5 Perhaps, one might
reason that the Test of Time index is a reliable and the most
basic element in defining a discovery as a Classic. Yet, there
is no fixed Test of Time index to highlight significance of the
new findings. The importance of some discoveries is self-evident, at least to the connoisseurs, as was the discovery of the
double-stranded helix by Watson and Crick to John Maddox,
the legendary editor of Nature (1966–1973 and 1980–1995).
John Maddox apparently accepted the article without an
­external peer-review because the correctness and significance
of the findings to him were self-evident.6
The efforts of the Editors of Circulation Research in
advocating scientific discoveries that are fundamental and
­
have stood the Test of Time is praiseworthy, particularly in
a scientific publishing environment whereby journals and the
articles are judged by their short-term citation index rather
than the true impact on the scientific progress. Unfortunately,
in judging significance of the discoveries the scientific society
often gives precedence to where it is published than the actual
content of the article. Yet, one might surmise that it would be
T
he discovery of the ACE2 gene broadened the scope of
the regulatory mechanisms that govern the biological
effects of the renin–angiotensin system in the cardiovascular system and beyond
The late Daniel E. Koshland Jr. (1920–2007), a former editor of Science (1985–1995), characterized scientific discoveries into 3 categories of Charge, Challenge, and Chance,
which he dubbed as The Cha-Cha-Cha Theory of Scientific
Discoveries.1 Citing Nobel laureate Albert Szent-Györgyi,
Dr Koshland described the first Cha, as to see what everyone else has seen and think what no one else has thought before. Charge solves the obvious problems, such as the laws of
heredity, which were delineated by Gregory Mendel and the
theory of gravity, which was developed by Sir Isaac Newton.
The second Cha refers to discovery of a new concept that
pulls together the accumulated facts that had remained unexplained, such as the description of base pairing in double
helix by Watson and Crick.2 The third Cha is for the serendipitous discoveries, which per Louis Pasteur favor the prepared mind.1 Sir Alexander Fleming observed clear spots on
petri dish and went on to discover penicillin from the mold
Penicillin notatum.
Scientific discoveries are typically incremental. The magnitude of increments follows a gradient from small to large. Major
discoveries are not made in a scientific vacuum or through the
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Center for Cardiovascular Genetics, Institute of Molecular
Medicine, University of Texas Health Sciences Center at Houston, and
Texas Heart Institute at St. Luke’s Episcopal Hospital, TX.
Correspondence to A.J. Marian, MD, Institute of Molecular Medicine,
University of Texas Health Sciences Center at Houston, Texas Heart
Institute at St. Luke’s Epsicopal Hospital, 6770 Bertner St, Suite C900A,
Houston, TX 77030. E-mail [email protected]
(Circ Res. 2013;112:1307-1309.)
© 2013 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.113.301271
1307
1308 Circulation Research May 10, 2013
Angiotensinogen
160
140
Renin
120
Angiotensin I
100
ACE2
ACE
ACE
80
Angiotensin II
(1-8)
60
Angiotensin 1-9
ACE2
Angiotensin 1-7
40
20
0
MAS1
AT1R
2 2 2
2 2
2
2
2 2 2 2 2
00 001 002 003 004 005 006 007 008 009 010 011 012
20
Figure 1. Number of the original articles, editorials, and
reviews published in the Biomedical Journals on ACE2
since 2000, when the original cloning of the ACE2 gene was
reported in Circulation Research.
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more challenging to have an article accepted for publication
in a subspecialty journal such as Circulation Research, where
top experts in the field peer-review the articles than in many
of the high impact factor general scientific journals, whereby
trendiness and potential breadth take precedence over robustness and depth.
The focus on the Classics also underscores the emphasis on
the fundamental discoveries that fulfill Dr Koshland’s Cha-ChaCha Theory of Scientific Discoveries as opposed to what is chic
or instigated by the excessive and often premature prominence
placed on translational research. The discoveries that have had
a major influence on drug development, medicine, and human
health have typically originated from addressing the fundamental
problems that are relevant to medicine, a point elegantly pointed
out by Goldstein and Brown7 in a recent perspective on a golden
era of Nobel laureates. The 9 Nobel Laureates who trained at
the National Institutes of Health between 1964 and 1972 made
their discoveries working on fundamental mechanisms.7 The
point is not to negate a major, if not the overarching, purpose
of biological sciences, which is to cure the human diseases.
The point is that to cure a disease, it is essential to understand
the fundamental mechanisms that govern its pathogenesis.
Excessive and premature emphasis on translational research
has the risk of diminishing the opportunities for fundamental
discoveries, and hence, the ultimate cure of human diseases, as
elegantly elaborated by physician-neuroscientist Huda Zoghbi
in a recent editorial in Science.8 Without such fundamental
understanding, translational research might simply emulate the
metaphoric blind men and an elephant.
Since its inception 60 years ago, the Editors-in-Chief of
Circulation Research have been visionary leaders who have
advocated publication of the fundamental scientific discoveries in the cardiovascular field. By scanning the list of published articles in the category of human molecular genetics,
one identifies a number of articles that merit to be considered
Classics. Among such articles, perhaps the discovery of angiotensin-converting enzyme (ACE2) is noteworthy and might
be categorized as a Classic.9 Since the first report of its cloning
and partial characterization in 2000 in Circulation Research,
955 original, editorial, and review articles about ACE2
have been published (Figure 1), and the original article by
Vasoconstriction (hypertension)
Proliferation
Hypertrophy
Fibrosis
Figure 2. Dual functions of the renin–angiotensin system with
opposing effects on cardiovascular biology. Renin converts
angiotensinogen to angiotensin (Ang) 1, which is then converted
by the converting enzyme angiotensin-converting enzyme (ACE)
to Ang II. Ang II through its type 1 receptor Ang II type I receptor
(AT1R) exerts deleterious effects on the cardiovascular system.
ACE2 converts Ang II to a heptapeptide Ang 1-7, which through
its receptor MAS1 counters the deleterious effects of ACE/Ang II/
AT1R pathway.
Donoghue et al9 has been cited nearly 700 times as of March
2013. Although it is probably too premature to judge the full
impact of this discovery on the practice of medicine, it has,
nonetheless, changed our simplistic vertical concept about the
renin-angiotensin-system (RAS) by pointing out the presence
of dual functions of the RAS with opposing effects in cardiovascular biology.
The scientific background for cloning of the human ACE2
by Donoghue et al9 and Tipnis et al10 was the strong evidence
for the presence of functionally active angiotensin (Ang) 1-7
in the brain. However, the enzyme(s) responsible for the generation of Ang 1-7, presumably through cleavage of Ang I
and Ang II, were not fully known. Donoghue et al cloned the
human ACE2 from a human heart failure ventricular cDNA
library and showed that it was predominantly expressed in the
endothelium in the heart, the kidney, and less so in the testis.9
Sequence analysis suggested that ACE and ACE2 exhibited
42% amino acid identity and had evolved through gene duplication. Despite sequence identity, however, ACE2 has a
distinct role in generating Ang 1-7 and less so, Ang 1-9 than
ACE. Although ACE generates Ang II (Ang 1–8) from Ang
I, ACE2 cleaves Ang II (1–8) to generate heptapeptide Ang
1-7 (Figure 2). The latter acts as a ligand through its recently
identified receptor MAS1, which is a G-protein–coupled receptor.11 Binding of Ang 1-7 to MAS1 receptors activates the
phospholipase C signaling pathway and leads to a number of
effects that are opposite to activation of the type 1 receptors
by Ang II type I receptor, such as smooth muscle relaxation,
hypotension, and protection against hypertrophy and fibrosis.
Thus, ACE2/Ang 1-7/MAS1 pathway provides for an endogenous counter-regulatory mechanism within the RAS, which
Marian The Discovery of the ACE2 Gene 1309
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balances the deleterious effects of the ACE/Ang II/Ang II type
I receptor axis.
Since its cloning ≈13 years ago, ACE2 has emerged as an
important regulator of the cardiovascular system, albeit the full
spectrum of its functions has yet to be recognized. Given the
role of the RAS in various physiological and pathological processes in multiple organs, the discovery and characterization of
the ACE2 pathway might have implications well beyond cardiovascular medicine. Perhaps, deletion of the Mas1 gene, coding
for the Ang 1-7 receptor, or the Ace2 gene provides glimpses, at
least in the mouse, into the biological significance of the ACE2/
Ang 1-7 MAS1 axis in the cardiovascular system (reviewed in
Santos et al12). Mice deficient in MAS1 or ACE2 exhibit cardiac systolic dysfunction, increased blood pressure, myocardial
interstitial fibrosis, endothelial dysfunction, susceptibility to
intravascular thrombosis, metabolic abnormalities, and various
other biological abnormalities that regulate the cardiovascular system.12–14 The discovery of ACE2 has also provided the
impetus for investigating potential clinical use of the MAS1
receptor agonists in the prevention and treatment of various
cardiovascular pathological states ranging from hypertension to
atherosclerosis. Efforts are underway to harness the potential
preventive and therapeutic effects of MAS receptor agonists in
several cardiovascular diseases. Notwithstanding the significance of the discovery of the ACE2 gene, targeted deletion of
the Ace2 in the mouse have led to conflicting data on the effects
of ACE2 on certain cardiovascular phenotype.14–16 Although the
initial report identified ACE2 as a major regulator of cardiac
function,14 subsequent studies in 2 independent Ace2 knockout
mouse models showed no discernible effect on cardiac function
or the blood pressure at the baseline15,16 (reviewed in Gurley
and Coffman17). In contrast, these studies identified ACE2 as a
major regulator of Ang II metabolism in vivo and consequently,
the response of cardiac hypertrophy to pressure overload and
the blood pressure to infusion of Ang II.15,16 Collectively, the
studies in the Ace2 knockout mouse models showed that ACE2
contributes to cardiovascular physiology and pathology through
its role in hydrolyzing Ang II and to some degree through synthesis of Ang 1-7.17 Given the broad spectrum of the biological effects of the RAS and the potential clinical significance
of balancing the deleterious effects of the ACE/Ang II/Ang II
type I receptor pathway by ACE2, through degradation of Ang
II and generation of Ang 1-7, one might catalog the discovery
of ACE2 pathway an endogenous negative regulator of the RAS
system as a Classic.
Sources of Funding
This study was supported in part by the grants from National Heart,
Lung, and Blood Institute (R01-HL088498 and R34HL105563),
National Institute on Aging(R21 AG038597-01), TexGen Fund from
Greater Houston Community Foundation, and George and Mary
Josephine Hamman Foundation.
Disclosures
None.
References
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Scientific Discovery. Science. 2007;317:761–762.
2. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for
deoxyribose nucleic acid. Nature. 1953;171:737–738.
3. Miersky AE. The discovery of DNA. Sci Am. 1968;218:78–88
4. Avery OT, MacLeod CM, McCarty M. Studies on the chemical transformation of penumococcal type. J Exp Med. 1944;79:137–158
5. Hershey AD, Chase M. Independent functions of viral protein and nucleic
acid in growth of bacteriophage. J Gen Physiol. 1952;36:39–56.
6.Maddox J. How genius can smooth the road to publication. Nature.
2003;426:119
7. Goldstein JL, Brown MS. History of science. A golden era of Nobel laureates. Science. 2012;338:1033–1034.
8. Zoghbi HY. The basics of translation. Science. 2013;339:250.
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Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S.
A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2)
converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1–E9.
10. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional
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Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes
EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther
T. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled
receptor MAS. Proc Natl Acad Sci USA. 2003;100:8258–8263
12. Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting
enzyme 2, angiotensin-(1–7) and MAS: new players of the renin-angiotensin system. J Endocrinol. 2013;216:R1–R17
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JS, Ramos AS, Rosa KT, Irigoyen MC, Bader M, Alenina N, Kitten GT,
Ferreira AJ. Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knockout mice. Hypertension. 2006;47:996–1002.
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Y, Shiota A, Sugano S, Takeda S, Rakugi H, Ogihara T. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced
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The Discovery of the ACE2 Gene
A.J. Marian
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Circ Res. 2013;112:1307-1309
doi: 10.1161/CIRCRESAHA.113.301271
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Copyright © 2013 American Heart Association, Inc. All rights reserved.
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