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Published ahead of print on August 11, 2005, doi:10.1165/rcmb.2005-0046OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 5, November 2005, 513-520

A more recent version of this article appeared on November 1, 2005
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Submitted on January 31, 2005
Revised on August 11, 2005

Involvement of Calpain-Calpastatin in Cigarette Smoke-induced Inhibition of Lung Endothelial NOS

Zhaoqiang Cui1, Zhaosheng Han1, Zhaozhong Li1, Hanbo Hu1, Jawaharlal M Patel2, Veena Antony2, Edward R Block2, and Yunchao Su1*

1 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA, 2 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA; Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA

* To whom correspondence should be addressed. E-mail: ysu{at}ufl.edu.

We reported that cigarette smoke extract (CSE) causes decreases in the activity and expression of endothelial nitric oxide synthase (eNOS) and calpain activity in pulmonary artery endothelial cells (PAEC). Calpains are a family of calcium-dependent endopeptidases and their specific endogenous inhibitor is calpastatin. In this study, we evaluated the role of calpain-calpastatin in CSE-induced decrease in eNOS gene expression. PAEC were incubated with 5-10% CSE for 2-24h, eNOS gene transcription rate, eNOS mRNA half-life, activity and protein contents of calpain and calpastatin were measured. Incubation of PAEC with CSE caused significant decreases in eNOS gene transcription and calpain activity and an increase in calpastatin protein content. eNOS mRNA half-life was not significantly altered by CSE. To investigate whether CSE-induced inhibition of eNOS gene expression is caused by decreased calpain activity due to increase in calpastatin protein content. We cloned calpastatin gene from PAEC and constructed adenovirus-vectors containing calpastatin. Overexpression of calpastatin mimics the inhibitory effects of CSE on calpain activity and on activity, protein and mRNA of eNOS. Cell permeable calpain inhibitor, calpastatin peptide, inhibits acetylcholine-induced endothelium-dependent relaxation of pulmonary artery. Incubation of PAEC with an antisense oligodeoxyribonucleotide (ODN) of calpastatin prevented CSE-induced increases in calpastatin protein and CSE-induced decreases in calpain activity, eNOS gene transcription, activity and protein content of eNOS, and in NO release. These results indicate that CSE-induced inhibition of eNOS expression in PAEC is caused by calpain inhibition due to an increase in calpastatin protein content.




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Y. Su, Z. Cui, Z. Li, and E. R. Block
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FASEB J, July 1, 2006; 20(9): 1443 - 1451.
[Abstract] [Full Text] [PDF]


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