Published online before print January 16, 2003, doi: 10.1161/01.RES.0000056770.30922.E6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Molecular Medicine |
Oxygen Sensing by Primary Cardiac Fibroblasts
A Key Role of p21Waf1/Cip1/Sdi1
From the Laboratory of Molecular Medicine (S.R., S.K., M.A., M.B., S.P., D.L., N.S., M.V., C.K.S.), Division of Transplantation (A.A.B., C.G.O.), Department of Surgery, and the Department of Physiology/Cell Biology (S.V.S., A.S.), Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus.
Correspondence to Dr Chandan K. Sen, Associate Director, 512 Davis Heart and Lung Research Institute, 473 W 12th Ave, Columbus, OH 43210. E-mail sen-1{at}medctr.osu.edu
In mammalian organs under normoxic conditions, O2 concentration ranges from 12% to <0.5%, with O2 
14% in arterial blood and <10% in the myocardium. During mild hypoxia, myocardial O2 drops to 1% to 3% or lower. In response to chronic moderate hypoxia, cells adjust their normoxia set point such that reoxygenation-dependent relative elevation of PO2 results in perceived hyperoxia. We hypothesized that O2, even in marginal relative excess of the PO2 to which cardiac cells are adjusted, results in activation of specific signal transduction pathways that alter the phenotype and function of these cells. To test this hypothesis, cardiac fibroblasts (CFs) isolated from adult murine ventricle were cultured in 10% or 21% O2 (hyperoxia relative to the PO2 to which cells are adjusted in vivo) and were compared with those cultured in 3% O2 (mild hypoxia). Compared with cells cultured in 3% O2, cells that were cultured in 10% or 21% O2 demonstrated remarkable reversible G2/M arrest and a phenotype indicative of differentiation to myofibroblasts. These effects were independent of NADPH oxidase function. CFs exposed to high O2 exhibited higher levels of reactive oxygen species production. The molecular signature response to perceived hyperoxia included (1) induction of p21, cyclin D1, cyclin D2, cyclin G1, Fos-related antigen-2, and transforming growth factor-ß1, (2) lowered telomerase activity, and (3) activation of transforming growth factor-ß1 and p38 mitogen-activated protein kinase. CFs deficient in p21 were resistant to such O2 sensitivity. This study raises the vital broad-based issue of controlling ambient O2 during the culture of primary cells isolated from organs.
Key Words: redox • free radicals • heart • cell culture
This article has been cited by other articles:
 |
|
 |
|
  L. C. McSpadden, R. D. Kirkton, and N. Bursac Electrotonic loading of anisotropic cardiac monolayers by unexcitable cells depends on connexin type and expression level Am J Physiol Cell Physiol, August 1, 2009; 297(2): C339 - C351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. NONOMURA, F. MIZOGUCHI, A. SUZUKI, T. NANKI, H. KATO, N. MIYASAKA, and H. KOHSAKA Hypoxia-induced Abrogation of Contact-dependent Inhibition of Rheumatoid Arthritis Synovial Fibroblast Proliferation J Rheumatol, April 1, 2009; 36(4): 698 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, S.-R. A. Hussain, S. Biswas, A. Azad, C. Rink, S. Gnyawali, S. Shilo, G. J. Nuovo, and C. K. Sen MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue Cardiovasc Res, April 1, 2009; 82(1): 21 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun Myocardial repair/remodelling following infarction: roles of local factors Cardiovasc Res, February 15, 2009; 81(3): 482 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, H. Cui, T. K. Kundu, W. Alzawahra, and J. L. Zweier Nitric Oxide Production from Nitrite Occurs Primarily in Tissues Not in the Blood: CRITICAL ROLE OF XANTHINE OXIDASE AND ALDEHYDE OXIDASE J. Biol. Chem., June 27, 2008; 283(26): 17855 - 17863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, T. Rink, J. Radtke, W. T. Williams, S. Biswas, R. Schnitt, A. R. Strauch, and C. K. Sen p21waf1/cip1/sdi1 as a Central Regulator of Inducible Smooth Muscle Actin Expression and Differentiation of Cardiac Fibroblasts to Myofibroblasts Mol. Biol. Cell, December 1, 2007; 18(12): 4837 - 4846. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, B. Liu, S. Zhou, Y.-R. Chen, Y. Deng, J. L. Zweier, and G. He Ischemic preconditioning prevents in vivo hyperoxygenation in postischemic myocardium with preservation of mitochondrial oxygen consumption Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1442 - H1450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Kuhn, S. Roy, J. Radtke, S. Khanna, and C. K. Sen Laser microdissection and capture of pure cardiomyocytes and fibroblasts from infarcted heart regions: perceived hyperoxia induces p21 in peri-infarct myocytes Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1245 - H1253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Li, M. Petrimpol, K. D. Molle, M. N. Hall, E. J. Battegay, and R. Humar Hypoxia-Induced Endothelial Proliferation Requires Both mTORC1 and mTORC2 Circ. Res., January 5, 2007; 100(1): 79 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Sen, S. Khanna, and S. Roy Perceived hyperoxia: Oxygen-induced remodeling of the reoxygenated heart Cardiovasc Res, July 15, 2006; 71(2): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Kuhn, S. Roy, J. Radtke, S. Gupta, and C. K. Sen Laser microdissection and pressure-catapulting technique to study gene expression in the reoxygenated myocardium Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2625 - H2632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, D. E. Kuhn, C. Rink, W. T. Williams, J. L. Zweier, and C. K. Sen Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix Physiol Genomics, May 16, 2006; 25(3): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miragoli, G. Gaudesius, and S. Rohr Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts Circ. Res., March 31, 2006; 98(6): 801 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ernens, S. J. Goodfellow, F. Innes, N. S. Kenneth, L. E. Derblay, R. J. White, and P. H. Scott Hypoxic stress suppresses RNA polymerase III recruitment and tRNA gene transcription in cardiomyocytes Nucleic Acids Res., January 10, 2006; 34(1): 286 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Khanna, S. Roy, A. Slivka, T. K.S. Craft, S. Chaki, C. Rink, M. A. Notestine, A. C. DeVries, N. L. Parinandi, and C. K. Sen Neuroprotective Properties of the Natural Vitamin E {alpha}-Tocotrienol Stroke, October 1, 2005; 36(10): e144 - e152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, A. Samouilov, X. Liu, and J. L. Zweier Characterization of the Effects of Oxygen on Xanthine Oxidase-mediated Nitric Oxide Formation J. Biol. Chem., April 23, 2004; 279(17): 16939 - 16946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Roy, S. Khanna, W. A. Wallace, J. Lappalainen, C. Rink, A. J. Cardounel, J. L. Zweier, and C. K. Sen Characterization of Perceived Hyperoxia in Isolated Primary Cardiac Fibroblasts and in the Reoxygenated Heart J. Biol. Chem., November 21, 2003; 278(47): 47129 - 47135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gaudesius, M. Miragoli, S. P. Thomas, and S. Rohr Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin Circ. Res., September 5, 2003; 93(5): 421 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhang, S. Sharma, L. X. Zhu, T. Kogai, J. M. Hershman, G. A. Brent, S. M. Dubinett, and M. Huang Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells Cancer Res., August 15, 2003; 63(16): 5065 - 5072. [Abstract] [Full Text] [PDF]
|
|