Cardiovascular Research Advance Access published August 12, New pathophysiological function of protein phosphatase 2A?

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1 Cardiovascular Research Advance Access published August 12, EDITORIAL 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 Tel: (0) , Fax: (0) , * joachim.neumann@medizin.uni-halle.de See article by Larsen et al. (pages XXX XXX) in this issue. Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

2 2 In this issue of the Journal, there is an interesting study by Larsen and coworkers 1. The authors provide 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 in order 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. Based on the model and the clinical feature of pulmonary hypertension, one would have expected only a right ventricular increase in phosphatase activity. 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 MCIP, a protein inhibitor of calcineurin, this hypertrophy can also be antagonised (for review 2 ). Moreover, there is evidence that increased expression of the catalytic subunit of PP1α occurs in human heart failure 3,4, and mice with overexpression of the catalytic subunit of PP1α 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, increased PP1 activity and cardiac hypertrophy is noted 5. Similarly, if I-2 of PP1

3 3 is overexpressed, the heart exhibits a hypercontractile state under basal conditions, probably because the phosphorylation state of phospholamban is enhanced 6. Some studies on the cardiac role on PP2A, which occurs as a dimer or trimer (Fig. 1), have also been performed (for review 7 ). For instance, overexpression of a dominant negative mutant of the structural A-subunit of PP2A increases 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 (Fig. 1). Moreover, inhibition of PP2A with a drug, fostriecin, protected rabbit hearts against ischemia 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 Fig. 1). One can speculate that a drug such as fostriecin that is able to decrease 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. While it is well established that proteins like I-1 PP2A or I-2 PP2A 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 PP1 activity to some extent 14. In summary, the paper by Larsen et al. opens a new field of research into a pathophysiological role of PP2A.

4 References 4 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 doi: /cvr/cvn Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 2006; 7: 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: 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: 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: 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; Janssens V, Longin S, Goris J (2008) PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 2000; 33: 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 H 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: 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: 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: Larsen AK, Escargueil AE, Skladanowski A (2003) Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol Ther 99: 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: 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:

5 5 Figure Legend: PP2A is composed of three subunits (A, B, C = catalytic subunits). 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. PP2A Fig. 1? hypoxia heart failure?? A C B increased expression decreased phosphorylation of regulatory proteins