Published online before print January 18, 2007, doi: 10.1161/01.RES.0000258116.60404.ad
© 2007 American Heart Association, Inc.
Cellular Biology |
p38-MAPK Induced Dephosphorylation of 
-Tropomyosin Is Associated With Depression of Myocardial Sarcomeric Tension and ATPase Activity
From the Department of Physiology and Biophysics (S.V., C.M.W., P.P.d.T., R.J.S.), Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago; Departments of Anesthesiology and Medicine (A.O., M.L., Y.W.), David Geffen School of Medicine, University of California at Los Angeles.
Correspondence to R. John Solaro, PhD, Department of Physiology and Biophysics, (M/C 901), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612-7342. E-mail solarorj{at}uic.edu
Our objective in work presented here was to understand the mechanisms by which activated p38
MAPK depresses myocardial contractility. To test the hypothesis that activation of p38 MAPK directly influences sarcomeric function, we used transgenic mouse models with hearts in which p38 MAPK was constitutively turned on by an upstream activator (MKK6bE). These hearts demonstrated a significant depression in ejection fraction after induction of the transgene. We also studied hearts of mice expressing a dominant negative p38 MAPK. Simultaneous determination of tension and ATPase activity of detergent-skinned fiber bundles from left ventricular papillary muscle demonstrated a significant inhibition of both maximum tension and ATPase activity in the transgenic-MKK6bE hearts. Fibers from hearts expressing dominant negative p38 MAPK demonstrated no significant change in tension or ATPase activity. There were no significant changes in phosphorylation level of troponin-T3 and troponin-T4, or myosin light chain 2. However, compared with controls, there was a significant depression in levels of phosphorylation of -tropomyosin and troponin I in fiber bundles from transgenic-MKK6bE hearts, but not from dominant negative p38 MAPK hearts. Our experiments also showed that p38 MAPK colocalizes with -actinin at the Z-disc and complexes with protein phosphatases (PP2, PP2ß). These data are the first to indicate that chronic activation of p38 MAPK directly depresses sarcomeric function in association with decreased phosphorylation of -tropomyosin.
Key Words: heart failure • myofilaments • protein phosphatase • tropomyosin kinase
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