Table of Contents
Journal of Signal Transduction
Volume 2012 (2012), Article ID 473410, 11 pages
Research Article

Contractile Activity Regulates Inducible Nitric Oxide Synthase Expression and NOi Production in Cardiomyocytes via a FAK-Dependent Signaling Pathway

1Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153, USA
2Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA

Received 29 March 2012; Revised 6 June 2012; Accepted 6 June 2012

Academic Editor: J. Adolfo García-Sáinz

Copyright © 2012 Miensheng Chu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Intracellular nitric oxide (NOi) is a physiological regulator of excitation-contraction coupling, but is also involved in the development of cardiac dysfunction during hypertrophy and heart failure. To determine whether contractile activity regulates nitric oxide synthase (NOS) expression, spontaneously contracting, neonatal rat ventricular myocytes (NRVM) were treat with L-type calcium channel blockers (nifedipine and verapamil) or myosin II ATPase inhibitors (butanedione monoxime (BDM) and blebbistatin) to produce contractile arrest. Both types of inhibitors significantly reduced iNOS but not eNOS expression, and also reduced NOi production. Inhibiting contractile activity also reduced focal adhesion kinase (FAK) and AKT phosphorylation. Contraction-induced iNOS expression required FAK and phosphatidylinositol 3-kinase (PI(3)K), as both PF573228 and LY294002 (10 μM, 24 h) eliminated contraction-induced iNOS expression. Similarly, shRNAs specific for FAK (shFAK) caused FAK knockdown, reduced AKT phosphorylation at T308 and S473, and reduced iNOS expression. In contrast, shRNA-mediated knockdown of PYK2, the other member of the FAK-family of protein tyrosine kinases, had much less of an effect. Conversely, overexpression of a constitutively active form of FAK (CD2-FAK) or AKT (Myr-AKT) reversed the inhibitory effect of BDM on iNOS expression and NOi production. Thus, contraction-induced iNOS expression and NOi production in NRVM are mediated via a FAK-PI(3)K-AKT signaling pathway.