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Cardiovascular Research Advance Access originally published online on August 12, 2008
Cardiovascular Research 2008 80(1):7-8; doi:10.1093/cvr/cvn204
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

New pathophysiological function of protein phosphatase 2A?

Joachim Neumann*

Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther Universität Halle-Wittenberg, Magdeburger Str. 4, Halle 06112, Germany

* Corresponding author. Tel: + 49 345 557 1686; fax: + 49 345 557 18 35. E-mail address: joachim.neumann{at}medizin.uni-halle.de

This editorial refers to ‘Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A’ by Larsen et al.,1 pp. 47–54, this issue.

In this issue of the Journal, there is an interesting study by Larsen et al.,1 which provides evidence that in pulmonary hypoxia a new mechanism might be operational that explains the deterioration of heart function in primary pulmonary hypertension. The authors chronically exposed mice to 10% oxygen to mimic hypoxia in patients. The authors had noted in previous studies that this degree of pulmonary hypoxia leads to slower cardiac relaxation, putatively due to reduced phosphorylation of phospholamban on amino acid serine 16. In the present report, they provide evidence that the activity of phosphatase 2A but not phosphatase 1 is enhanced in sarcoplasmic reticulum-enriched membranes from these hearts. This led to reduced phosphorylation of phospholamban, which could explain reduced cardiac contractility. Surprisingly, a similar increase in phosphatase activity was noted in left ventricular as well as in right ventricular preparations. On the basis of the model and the clinical feature of pulmonary hypertension, one would have expected an increase in phosphatase activity only in right ventricular preparation. This could indicate that a humoral mechanism, such as altered interleukin levels, increases transcriptional activity of the PP2A gene.

The role of serine/threonine phosphatases in the heart has gained considerable attention. For instance, it is well known that increased activity of calcineurin, also known as phosphatase 2B, leads to cardiac hypertrophy. If the animals are treated with an inhibitor on the enzyme (cyclosporine A), this hypertrophy is prevented. Also, if transgenic animals are engineered with additional overexpression of modulatory calcineurin-interacting protein, a protein inhibitor of calcineurin, this hypertrophy can also be antagonized (for review2). Moreover, there is evidence that increased expression of the catalytic subunit of PP1{alpha} occurs in human heart failure3,4, and mice with overexpression of the catalytic subunit of PP1{alpha} also exhibit hypertrophy, fibrosis, and increased mortality.5 If the phosphatase activity is reduced by use of an adenovirus, the phenotype of the animals is rescued.5 On the other hand, if the protein inhibitor of PP1, namely I-1, is knocked out, an increased PP1 activity and cardiac hypertrophy is noted.5 Similarly, if I-2 of PP1 is overexpressed, the heart exhibits a hypercontractile state under basal conditions, probably because the phosphorylation of phospholamban is enhanced.6

Some studies have also been performed on the cardiac role on PP2A, which occurs as a dimer or trimer (Figure 1; for review7). For instance, overexpression of a dominant negative mutant of the structural A-subunit of PP2A increases the PP2A activity, and this leads to cardiac hypertrophy.8 The function of the regulatory B-subunit has not yet been studied by overexpression in the heart (Figure 1). Moreover, inhibition of PP2A with a drug such as fostriecin protected rabbits' hearts against ischaemia.9 If the catalytic subunit of PP2A is overexpressed, this leads to cardiac hypertrophy, impaired cardiac function, and decreased phosphorylation of cardiac regulatory proteins like phospholamban and the inhibitory subunit of troponin.10 In addition, in at least some animal models of cardiac hypertrophy, increased activity of PP2A has been observed.11 Thus, it is interesting that PP2A can apparently also be regulated by hypoxia (see Figure 1). One can speculate that a drug such as fostriecin that is able to decrease the PP2A activity might be beneficial in primary pulmonary hypertension. However, this drug is usually used in patients suffering from carcinoma. In fact, fostriecin has other effects besides phosphatase inhibition, including effects on topoisomerases.12 Hence, PP2A might be an interesting target for future pharmaceutical research to design organic compounds that selectively inhibit this enzyme. Although it is well established that proteins like I-1PP2A or I-2PP2A exist,13 it cannot be predicted whether these would be useful for gene therapy of primary pulmonary hypertension or chronic obstructive pulmonary disease as they are known to increase the PP1 activity to some extent14. In summary, the paper by Larsen et al. opens a new field of research into a pathophysiological role of PP2A.


Figure 1
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  		Figure 1 PP2A is composed of three catalytic subunits (A, B, and C). Heart failure and/or hypoxia lead to increased expression of the C subunit and thereby increased phosphatase activity, which results in decreased phosphorylation and hence decreased function of cardiac regulatory proteins. For further details, see text.

 

   Notes
 
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.


   References
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 References
 

  1. Larsen KO, Lygren B, Sjaastad I, Krobert KA, Arnkværn K, Florholmen G, et al. Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A. Cardiovasc Res (2008) 80:47–54.[Abstract/Free Full Text]
  2. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol (2006) 7:589–600.[CrossRef][Web of Science][Medline]
  3. Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, et al. Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol (1997) 29:265–272.[CrossRef][Web of Science][Medline]
  4. Mishra S, Gupta RC, Tiwari N, Sharow VG, Sabbah HN. Molecular mechanisms of reduced sarcoplasmic reticulum Ca2+ uptake in human failing left ventricular myocardium. J Heart Lung Transplant (2002) 21:366–373.[CrossRef][Web of Science][Medline]
  5. Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, et al. Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol (2002) 22:4124–4135.[Abstract/Free Full Text]
  6. Kirchhefer U, Baba HA, Boknik P, Breeden KM, Mavila N, Brüchert N, et al. Enhanced cardiac function in mice overexpressing protein phosphatase inhibitor-2. Cardiovasc Res (2005) 68:98–108.[Abstract/Free Full Text]
  7. Janssens V, Longin S, Goris J. (2008) PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci (2000) 33:113–121.
  8. Brewis N, Ohst K, Fields K, Rapacciuolo A, Chou D, Bloor C, et al. Dilated cardiomyopathy in transgenic mice expressing a mutant A subunit of protein phosphatase 2A. Am J Physiol (2000) 279:H1307–H1318.[Web of Science]
  9. Weinbrenner C, Baines CP, Liu GS, Armstrong SC, Ganote CE, Walsh AH, et al. Fostriecin, an inhibitor of protein phosphatase 2A, limits myocardial infarct size even when administered after onset of ischemia. Circulation (1998) 98:899–905.[Abstract/Free Full Text]
  10. Gergs U, Boknik P, Buchwalow I, Fabritz L, Matus M, Justus I, et al. Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function. J Biol Chem (2004) 279:40827–40834.[Abstract/Free Full Text]
  11. Bokník P, Fockenbrock M, Herzig S, Knapp J, Linck B, Lüss H, et al. Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation. Naunyn Schmiedebergs Arch Pharmacol (2000) 362:222–231.[CrossRef][Web of Science][Medline]
  12. Larsen AK, Escargueil AE, Skladanowski A. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol Ther (2003) 99:167–181.[CrossRef][Web of Science][Medline]
  13. Li M, Makkinje A, Damuni Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J Biol Chem (1996) 271:11059–11062.[Abstract/Free Full Text]
  14. Katayose Y, Li M, Al-Murrani SWK, Shenolikar S, Damuni Z. Protein phosphatase 2A inhibitors, I1PP2A and I2PP2A, associate with and modify the substrate specificity of protein phosphatase 1. J Biol Chem (2000) 275:9209–9214.[Abstract/Free Full Text]

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Related Article

Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A
Karl-Otto Larsen, Birgitte Lygren, Ivar Sjaastad, Kurt A. Krobert, Kristin Arnkværn, Geir Florholmen, Ann-Kristin Ruud Larsen, Finn Olav Levy, Kjetil Taskén, Ole Henning Skjønsberg, and Geir Christensen
Cardiovasc Res 2008 80: 47-54. [Abstract] [Full Text] [PDF]




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