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J. Biol. Chem., Vol. 280, Issue 25, 24135-24142, June 24, 2005

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Role of p90 Ribosomal S6 Kinase (p90RSK) in Reactive Oxygen Species and Protein Kinase C (PKC-)-mediated Cardiac Troponin I Phosphorylation^*

Seigo Itoh, Bo Ding, Christopher P. Bains, Nadan Wang, Yasuchika Takeishi¶, Thunder Jalili||, George L. King**, Richard A. Walsh, Chen Yan, and Jun-ichi Abe

From the Cardiovascular Research Institute, University of Rochester, Rochester, New York 14642, the Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, ^¶Yamagata University, Yamagata, Japan 990-9585, the ^||University of Utah, Salt Lake City, Utah 84112, ^**Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts 02215, and Case Western Reserve University, Cleveland, Ohio 44106

Protein kinase C (PKC)-induced phosphorylation of cardiac troponin I (cTnI) depresses the acto-myosin interaction and may be important during the progression of heart failure. Although both PKCII and PKC can phosphorylate cTnI, only PKC expression and activity are elevated in failing human myocardium during end-stage heart failure. Furthermore, although increased cTnI phosphorylation was observed in mice with cardiac-specific PKC II overexpression, no differences were observed in cTnI phosphorylation status between wild type and cardiac-specific PKC overexpression mice. A potentially important downstream effector of PKCs is p90 ribosomal S6 kinase (p90RSK), which plays an important role in cell growth by activating several transcription factors as well as Na⁺/H⁺ exchanger. Since both Ser²³ and Ser²⁴ of cTnI are contained in putative consensus sequences of p90RSK phosphorylation sites, we hypothesized that p90RSK is downstream from PKC II and can be a cTnI (Ser^23/24) kinase. p90RSK, but not ERK1/2 activation, was increased in PKCII overexpression mice but not in PKC overexpression mice. p90RSK could phosphorylate cTnI in vitro with high substrate affinity but not cardiac troponin T (cTnT). To confirm the role of p90RSK in cTnI phosphorylation in vivo, we generated adenovirus containing a dominant negative form of p90RSK (Ad-DN-p90RSK). We found that the inhibition of p90RSK prevented H₂O₂-mediated cTnI (Ser^23/24) phosphorylation but not ERK1/2 and PKC/II activation. Next, we generated cardiac-specific p90RSK transgenic mice and observed that cTnI (Ser^23/24) phosphorylation was significantly increased. LY333,531, a specific PKC inhibitor, inhibited both p90RSK and cTnI (Ser^23/24) phosphorylation by H₂ O₂. Taken together, our data support a new redox-sensitive mechanism regulating cTnI phosphorylation in cardiomyocytes.

Received for publication, November 17, 2004 , and in revised form, April 19, 2005.

^* This work was supported by grants from American Heart Association AHA Postdoctoral Fellowship, 0325769T (to S. I.) and Grant-in aid, 0455847T (to C. Y.) and by Grants HL-66919 and HL-65262 from the National Institutes of Health (to J.i.-A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Cardiology Unit, Box 679, 601 Elmwood Ave., University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. Tel.: 585-273-1686; Fax: 585-273-1497; E-mail: jun-ichi_abe{at}urmc.rochester.edu.

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