Published Online
on May 16, 2005

A more recent version of this article appeared on May 24, 2005

This Article Full Text (PDF) All Versions of this Article: 111/20/2596    most recent CIRCULATIONAHA.104.490979v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lancel, S. Articles by Neviere, R. Search for Related Content PubMed PubMed Citation Articles by Lancel, S. Articles by Neviere, R. Related Collections Contractile function Other heart failure Apoptosis

Submitted on July 8, 2004
Revised on January 14, 2005
Accepted on January 20, 2005

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Steve Lancel PhD, Olivier Joulin MD, Raphael Favory MD, Jean Francois Goossens PhD, Jérome Kluza PhD, Claude Chopin MD, Pierre Formstecher MD, PhD, Philippe Marchetti MD, PhD, and Remi Neviere MD, PhD^*

From EA 2689, CHRU, and Université de Lille 2, IFR 114 IMPRT (S.L., O.J., R.F., C.C., R.N.); INSERM U459 U524, IMPRT (J.K., P.F., P.M.); Laboratoire de Chimie analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2 (J.F.G.); and Département de Physiologie, Faculté de Médecine, Université de Lille 2 (S.L., O.J., R.F., R.N.), Lille, France.

^* To whom correspondence should be addressed. E-mail: rneviere{at}univ-lille2.fr.

Background--Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction.

Methods and Results--LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca²⁺. Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3-like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk- or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk.

Conclusions--The results show an important relationship between endotoxin-induced caspase activation and reduced contractile reserve and sarcomere disarray at the level of single LV cardiomyocytes.

Key words: apoptosis • myocardial contraction • myocytes, cardiac • inflammation • shock

This article has been cited by other articles:

				G. S. Supinski, M. P. Murphy, and L. A. Callahan MitoQ administration prevents endotoxin-induced cardiac dysfunction Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2009; 297(4): R1095 - R1102. [Abstract] [Full Text] [PDF]

				X. Li, Y. Li, L. Shan, E Shen, R. Chen, and T. Peng Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxaemia Cardiovasc Res, July 1, 2009; 83(1): 72 - 79. [Abstract] [Full Text] [PDF]

				C. Pavoine and F. Pecker Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology Cardiovasc Res, May 1, 2009; 82(2): 175 - 183. [Abstract] [Full Text] [PDF]

				J. Radhakrishnan, I. M. Ayoub, and R. J. Gazmuri Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1164 - H1174. [Abstract] [Full Text] [PDF]

				A. d. de Tassigny, A. Berdeaux, R. Souktani, P. Henry, and B. Ghaleh The volume-sensitive chloride channel inhibitors prevent both contractile dysfunction and apoptosis induced by doxorubicin through PI3kinase, Akt and Erk 1/2 Eur J Heart Fail, January 1, 2008; 10(1): 39 - 46. [Abstract] [Full Text] [PDF]

				D. L. Carlson, D. L. Maass, J. White, P. Sikes, and J. W. Horton Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury J Appl Physiol, July 1, 2007; 103(1): 323 - 330. [Abstract] [Full Text] [PDF]

				F. Hua, T. Ha, J. Ma, Y. Li, J. Kelley, X. Gao, I. W. Browder, R. L. Kao, D. L. Williams, and C. Li Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism J. Immunol., June 1, 2007; 178(11): 7317 - 7324. [Abstract] [Full Text] [PDF]

				D. Carlson, D. L. Maass, D. J. White, J. Tan, and J. W. Horton Antioxidant vitamin therapy alters sepsis-related apoptotic myocardial activity and inflammatory responses Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2779 - H2789. [Abstract] [Full Text] [PDF]

				T. Ha, F. Hua, D. Grant, Y. Xia, J. Ma, X. Gao, J. Kelley, D. L. Williams, J. Kalbfleisch, I. W. Browder, et al. Glucan phosphate attenuates cardiac dysfunction and inhibits cardiac MIF expression and apoptosis in septic mice Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1910 - H1918. [Abstract] [Full Text] [PDF]

				J. Larche, S. Lancel, S. M. Hassoun, R. Favory, B. Decoster, P. Marchetti, C. Chopin, and R. Neviere Inhibition of Mitochondrial Permeability Transition Prevents Sepsis-Induced Myocardial Dysfunction and Mortality J. Am. Coll. Cardiol., July 18, 2006; 48(2): 377 - 385. [Abstract] [Full Text] [PDF]

				G. S. Supinski and L. A. Callahan Polyethylene Glycol-Superoxide Dismutase Prevents Endotoxin-induced Cardiac Dysfunction Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1240 - 1247. [Abstract] [Full Text] [PDF]