Published online before print March 3, 2003, doi: 10.1161/01.CIR.0000055319.94801.FC
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(Circulation. 2003;107:1424.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide
Impact on Cardiac Myocyte Hypertrophy
From the Departments of Cardiology and Angiology (J.H., T. Kempf, A.H., H.D., K.C.W.) and Molecular and Cellular Physiology (T. Kraft), Hannover Medical School, Hannover, Germany; the Institute of Pathophysiology (H.M.) and the Department of Cardiothoracic Surgery (R.J.S.), University of Halle-Wittenberg, Halle-Wittenberg, Germany; the Friedrich-Miescher Institute (P.C.), Basel, Switzerland; and the Institute of Clinical Biochemistry and Pathobiochemistry (S.M.L.), University of Würzburg, Würzburg, Germany.
Correspondence to Priv-Doz Dr med Kai C. Wollert, Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Straße 1, 30625 Hannover, Germany. E-mail wollert.kai{at}mh-hannover.de
Background— In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure.
Methods and Results— As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeleton-associated muscle LIM protein (MLP) in endothelin-1 (ET-1)–stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (-49%, P<0.01) and protein (-52%, P<0.01) abundance in ET-1–treated cardiomyocytes via cGMP-dependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1ß and IFN-
downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (-52%, P<0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes.
Conclusions— NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.
Key Words: nitric oxide • cytoskeleton • myocytes • hypertrophy
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