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Two ACEs and a heart

Naturevolume 417pages799801 (2002) | Download Citation

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Cardiovascular diseases are some of the biggest killers in the developed world. The discovery of a new enzyme that affects cardiac function might provide fresh insight into heart disease.

For years now, scientists have thought that they understand the formation, function and fate of the eight-amino-acid peptide angiotensin II. This peptide is the result of the progressive degradation of a precursor protein, angiotensinogen, by the enzymes renin and angiotensin-converting enzyme (ACE). Once formed, angiotensin II is a master regulator of body physiology, raising blood pressure by coordinated effects on the heart, blood vessels and kidneys. The importance of angiotensin II is also implied by the wide clinical use of ACE inhibitors — drugs that reduce the formation of angiotensin II — to treat high blood pressure, heart failure and even some of the destructive effects of diabetes. But, as Crackower and colleagues make clear on page 822 of this issue1, the 'renin–angiotensin' system is even more complicated than was thought. It seems that the recently discovered enzyme ACE2 also has a say in how the heart functions.

The story begins in 2000, with the discovery2,3 of ACE2 as an enzyme similar to ACE — both are carboxypeptidases, meaning that they catalyse the shortening of peptides from their carboxy-terminal ends. But whereas ACE cleaves two amino acids at a time, ACE2 shortens peptides by only one amino acid. The upshot is that angiotensin peptides come in several slightly different sizes, yet have very different effects. Angiotensin I (with ten amino acids) is an intermediate peptide without significant biological effects (Fig. 1). Angiotensin I is thought to be converted to angiotensin 1-9 (with nine amino acids) by ACE2, but to the eight-amino-acid angiotensin II by ACE. Whereas angiotensin II stimulates blood-vessel constriction and raises blood pressure, angiotensin 1-9 has no known effects. Angiotensin 1-9 cannot be converted to angiotensin II by ACE2, but can be converted to angiotensin 1-7 (a blood-vessel dilator) by ACE. So it has been suggested that ACE2 prevents the formation of the blood-vessel constrictor angiotensin II.

Figure 1: Angiotensin peptides.
Figure 1

Blood-vessel constrictors are in blue; vessel dilators are in green. The enzyme renin catalyses the release of the ten-amino-acid peptide angiotensin I from the precursor protein angiotensinogen. Further catalysis by ACE produces the eight-amino-acid angiotensin II, which is a powerful vessel constrictor and results in higher blood pressure. ACE2 is thought to produce the nine-amino-acid angiotensin 1-9, which has no known effects but can be converted by ACE to angiotensin 1-7, a vessel dilator. So ACE2 has been proposed to reduce the formation of angiotensin II and to oppose the increase in blood pressure that is mediated by ACE and angiotensin II. Crackower et al.1 find that the ACE2 gene is found on a region of the rat X chromosome that has been implicated in high blood pressure. Yet knocking out ACE2 in mice does not raise blood pressure, but instead leads to malfunctioning heart muscle.

But what do the effects of ACE2 on angiotensin peptides mean in terms of physiology? A first hint was the finding that this enzyme is expressed solely in the heart, kidneys and testes2,3. But it is the paper by Crackower et al.1 that provides the first really compelling evidence of ACE2's biological role. First, the authors present gene-mapping studies designed to find the location of the ACE2 gene in the rat genome, specifically on the rat X chromosome. The reason was that studies of several rat 'models' of high blood pressure had suggested that the X chromosome contains a particular region (perhaps even a particular gene) that is important in the heritability and induction of raised blood pressure. Indeed, Crackower et al. found that the ACE2 gene maps to the same region of the X chromosome that has been implicated in three such models. Moreover, ACE2 protein levels were reduced in these models.

So is ACE2 involved in controlling blood pressure? To find out, Crackower et al. created 'knockout' mice lacking all ACE2 protein. Mice lacking the ACE protein have very low blood pressure4,5. Thus, one might imagine that knocking out ACE2 has the opposite effect — high blood pressure — as suggested by the rat models. In fact, the authors found that blood pressure is normal in the ACE2-knockout mice. But surprisingly, and unlike the ACE-deficient mice, the ACE2-knockout animals develop abnormal (pathological) heart function as they age. Specifically, the heart muscle develops a significant defect in both the speed and the overall percentage of contraction. Unusually, though, the hearts show only mild physical changes, with virtually no increase in cardiac scarring.

Why don't the hearts of the ACE2-knockout mice function properly? Crackower et al. found that the lack of ACE2 leads to an increase in angiotensin II levels, and suggest that this may, in part, incite the pathology (through heart-specific mechanisms that apparently would not involve an effect on blood pressure). It is wise to keep an open mind, however. The increased levels of angiotensin II are significant but relatively modest, and might be expected as a result, rather than a cause, of heart dysfunction.

The authors also engineered 'double-knockout' mice that lack both ACE and ACE2. These animals are identical to the ACE-knockout mice: they have low blood pressure and no heart failure. They presumably make little angiotensin II (because they lack ACE). So Crackower et al. again suggest that angiotensin II contributes to the heart-muscle dysfunction seen in the animals lacking just ACE2. The difficulty is that the double-knockout mice also have a much lower blood pressure than the ACE2-deficient animals. Low blood pressure is good for the heart and is often associated with a slower development of heart failure. So it remains to be seen whether the normal heart function in the double-knockout mice results directly from the lack of cardiac angiotensin II or indirectly from the protective effects of low blood pressure.

Finally, Crackower et al. studied heart development in fruitflies (Drosophila melanogaster). Fruitflies have two ACE2-like enzymes, and the authors looked at mutants that lack one of these, ACER. The mutants die at an early embryonic stage, so the authors analysed the genes expressed by the very earliest heart progenitor cells. They found that two of the genes, named Eve and Tinman, show an abnormal cellular pattern of expression. This implies that ACER is needed for normal heart development in D. melanogaster. Exactly how this relates to mammalian biology is unclear. ACE2-deficient mice are born alive; embryonic heart development seems normal and the animals do not develop heart disease until several months after birth. So there seem to be differences between the roles of ACER in flies and ACE2 in mammals — another intriguing issue for further study.

So where are we now in understanding the role of ACE2? Perhaps the most important finding in the paper by Crackower et al. is that the mammalian protein affects heart function. Hence, the absence (and perhaps, by extension, the dysfunction) of ACE2 may contribute to heart disease — a killer that claims the lives of nearly one in two people in the developed world. But we still need to know exactly how ACE2 works, and whether and how it helps to control blood pressure in humans. Another question is whether the abnormal heart function seen in the ACE2-knockout mice results from abnormalities in angiotensin peptide levels or whether another, unknown, substrate of ACE2 is affected.

The paper by Crackower et al. embodies an important theme in modern angiotensin-related research: an increasing awareness of the many different aspects of physiology that are regulated by the renin–angiotensin system. That ACE2 somehow affects heart-muscle function is now a fact. Investigation of whether this is mediated through angiotensin II, arguably the central regulator of the human cardiovascular system, or some other mechanism will be the next chapter in the story.

References

  1. 1

    Crackower, M. A. et al. Nature 417, 822–828 (2002).

  2. 2

    Tipnis, S. R. et al. J. Biol. Chem. 275, 33238–33243 (2000).

  3. 3

    Donoghue, M. et al. Circ. Res. 87, e1–e9 (2000).

  4. 4

    Krege, J. H. et al. Nature 375, 146–148 (1995).

  5. 5

    Esther, C. R. Jr et al. Lab. Invest. 74, 953–965 (1996).

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  1. Department of Pathology, Emory University, Atlanta, 30322, Georgia, USA

    • Kenneth E. Bernstein

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Correspondence to Kenneth E. Bernstein.

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https://doi.org/10.1038/417799a

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