Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A.

Abstract

Earlier investigations in our lab indicated an anti-adrenergic effect induced by activation of p21-activated kinase (Pak-1) and protein phosphatase 2A (PP2A). Our objective was to test the hypothesis that Pak-1/PP2A is a signaling cascade controlling stress-induced cardiac growth. We determined the effects of ablation of the Pak-1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. Wild-type (WT) and Pak-1-knockout (Pak-1-KO) mice were randomized into six groups to receive either ISO, saline (CTRL), or ISO and FR180204, a selective inhibitor of Erk1/2. Echocardiography revealed that hearts of the Pak-1-KO/ISO group had increased LV fractional shortening, reduced LV chamber volume in diastole and systole, increased cardiac hypertrophy, and enhanced transmitral early filling deceleration time, compared to all other groups. The changes were associated with an increase in relative Erk1/2 activation in Pak-1-KO/ISO mice versus all other groups. ISO-induced cardiac hypertrophy and Erk1/2 activation in Pak-1-KO/ISO were attenuated when the selective Erk1/2 inhibitor FR180204 was administered. Immunoprecipitation showed an association between Pak-1, PP2A, and Erk1/2. Cardiac myocytes infected with an adenoviral vector expressing constitutively active Pak-1 showed a repression of Erk1/2 activation. p38 MAPK phosphorylation was decreased in Pak-1-KO/ISO and Pak-1-KO/CTRL mice compared to WT. Levels of phosphorylated PP2A were increased in ISO-treated Pak-1-KO mice, indicating reduced phosphatase activity. Maximum Ca(2+)-activated tension in detergent-extracted bundles of papillary fibers from ISO-treated Pak-1-KO mice was higher than in all other groups. Analysis of cTnI phosphorylation indicated that compared to WT, ISO-induced phosphorylation of cTnI was blunted in Pak-1-KO mice. Active Pak-1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A.

• Authors: Domenico M Taglieri, Michelle M Monasky, Ivana Knezevic, Katherine A Sheehan, Ming Lei, Xin Wang, Jonathan Chernoff, Beata M Wolska, Yunbo Ke, R John Solaro
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 51 Issue 6 Pg. 988-96 (Dec 2011) ISSN: 1095-8584 [Electronic] England
• PMID: 21971074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2011 Elsevier Ltd. All rights reserved.

Chemical References

• FR 180204
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridazines
• p21-Activated Kinases
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Protein Phosphatase 2
• Isoproterenol
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomegaly (chemically induced, enzymology, genetics, pathology)
• Disease Models, Animal
• Echocardiography
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Knockout Techniques
• Isoproterenol (administration & dosage, adverse effects, pharmacology)
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Myofibrils (metabolism)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Phosphatase 2 (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Pyridazines (pharmacology)
• Signal Transduction
• p21-Activated Kinases (deficiency, genetics)