Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function.
Reversible protein phosphorylation is an essential regulatory mechanism in many cellular functions. In contrast to protein kinases, the role and regulation of protein phosphatases has remained ambiguous. To address this issue, we generated transgenic mice that overexpress the catalytic subunit alpha of protein phosphatase 2A (PP2A) (PP2Acalpha) in the heart driven by the alpha-myosin heavy chain promoter. Overexpression of the PP2Acalpha gene in the heart led to increased levels of the transgene both at RNA and protein levels. This was accompanied by a significant increase of PP2A enzyme activity in the myocardium. Morphological analysis revealed isles of necrosis and fibrosis. The phosphorylation state of phospholamban, troponin inhibitor, and eukaryotic elongation factor 2 was reduced significantly. The expression of junctional (calsequestrin) and free SR proteins (SERCA and phospholamban) was not altered. Whereas no increase in morbidity or mortality was noted, transgenic mice developed cardiac hypertrophy and reduced contractility of the heart, as well as cardiac dilatation as shown by biplane echocardiography. Taken together, these findings are indicative of the fundamental role of PP2A in cardiac function and imply that disturbances in protein phosphatases expression and activity may cause or aggravate the course of cardiac diseases.
Gergs
Ulrich
U
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Universitätsklinikum, 48129 Münster, Germany.
Boknik
Peter
P
Buchwalow
Igor
I
Fabritz
Larissa
L
Matus
Marek
M
Justus
Isabel
I
Hanske
Gabriela
G
Schmitz
Wilhelm
W
Neumann
Joachim
J
D000199:Actins / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005355:Fibrosis; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D012313:RNA / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019076:Transgenes
D000199:Actins; D018076:DNA, Complementary; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D012313:RNA; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002118:Calcium