HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/6/H2169    most recent 00199.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Han, H. Articles by Wang, Z. Search for Related Content PubMed PubMed Citation Articles by Han, H. Articles by Wang, Z.

Progressive apoptotic cell death triggered by transient oxidative insult in H9c2 rat ventricular cells: a novel pattern of apoptosis and the mechanisms

¹Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8; and ²Department of Medicine, University of Montreal, Montreal, Quebec, Canada H3C 3J7

Submitted 6 March 2003 ; accepted in final form 14 January 2004

Many pathophysiological processes are associated with oxidative stress and progressive cell death. Oxidative stress is an apoptotic inducer that is known to cause rapid cell death. Here we show that a brief oxidative insult (5-min exposure to 400 µM H₂O₂), although it did not kill H9c2 rat ventricular cells during the exposure, triggered an intracellular death cascade leading to delayed time-dependent cell death starting from 1 h after the insult had been withdrawn, and this post-H₂O₂ cell death cumulated gradually, reaching a maximum level 8 h after H₂O₂ withdrawal. By comparison, sustained exposure to H₂O₂ caused complete cell death within a narrow time frame (2 h). The time-dependent post-H₂O₂ cell death was typical of apoptosis, both morphologically (cell shrinkage and nuclear condensation) and biochemically (DNA fragmentation, extracellular exposure of phosphatidylserines, and caspase-3 activation). A dichlorofluorescein fluorescent signal showed a time-dependent endogenous increase of reactive oxygen species (ROS) production, which was almost abolished by inhibition of the mitochondrial electron transport chain. Application of antioxidants (vitamin E or DTT) before H₂O₂ addition or after H₂O₂ withdrawal prevented the H₂O₂-triggered progressive ROS production and apoptosis. Sequential appearance of events associated with activation of the mitochondrial death pathway was found, including progressive dissipation of mitochondrial membrane potential, cytochrome c release, and late activation of caspase-3. In conclusion, transient oxidative stress triggers an intrinsic program leading to self-sustained apoptosis in H9c2 cells via cumulative production of mitochondrial ROS and subsequent activation of the mitochondrial death pathway. This pattern of apoptosis may contribute to the progressive and long-lasting cell loss in some degenerative diseases.

mitochondria; hydrogen peroxide; antioxidants

This article has been cited by other articles:

				S. M. Davidson, D. M. Yellon, B. K. Lal, S. Varma, R. Zheng, P. J. Pappas, and W. N. Duran Does Hyperglycemia Reduce Proliferation or Increase Apoptosis? Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1486 - H1487. [Abstract] [Full Text] [PDF]