Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 218-225

Caspase Inhibition Prevents Cardiac Dysfunction and Heart Apoptosis in a Rat Model of Sepsis

RÉMI NEVIÈRE, HAROLD FAUVEL, CLAUDE CHOPIN, PIERRE FORMSTECHER, and PHILIPPE MARCHETTI

INSERM U459, Faculté de Médecine, EA 2689, Pavillon Vancostenobel, Faculté de Médecine, and Département de Physiologie, Faculté de Médecine, Lille Cedex, France

Despite intensive therapy, severe septic shock is commonly associated with myocardial dysfunction and death in humans. No new therapies have proven efficiency against cardiovascular alterations in sepsis. Here, we addressed the question of a beneficial effect of pharmacological inhibition of caspases on myocardial dysfunction following endotoxin treatment. Hearts from rats treated with endotoxin (10 mg/kg, intravenously) were isolated 4 h posttreatment for analysis. Assessment of myocardial contractility ex vivo and detection of apoptosis were performed. Hearts from endotoxin-treated rats displayed multiple caspase activities and also typical apoptosis pattern as detected by TUNEL, DNA fragmentation assays, and cytochrome c release as compared with control rats. z-VAD.fmk (3 mg/kg, intravenously), a broad spectrum caspase inhibitor (but not the irrelevant peptide z-FA.fmk), in coinjection with endotoxin, not only reduced caspase activities and nuclear apoptosis but also completely prevented endotoxin-induced myocardial dysfunction evaluated 4 h and even 14 h after endotoxin challenge. These data indicate that caspase activation plays an important role in myocardial cell dysfunction. Moreover, these results suggest that inhibitors of caspases may have important therapeutic applications in sepsis.

This article has been cited by other articles:

				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. Ronco, J. A. Kellum, R. Bellomo, and A. A. House Potential Interventions in Sepsis-Related Acute Kidney Injury Clin. J. Am. Soc. Nephrol., March 1, 2008; 3(2): 531 - 544. [Abstract] [Full Text] [PDF]

				G. S. Supinski, X. Ji, W. Wang, and L. A. Callahan The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction J Appl Physiol, April 1, 2007; 102(4): 1649 - 1657. [Abstract] [Full Text] [PDF]

				G. S. Supinski and L. A. Callahan Caspase activation contributes to endotoxin-induced diaphragm weakness J Appl Physiol, June 1, 2006; 100(6): 1770 - 1777. [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]

				J.-B. Park, I.-C. Park, S.-J. Park, H.-O. Jin, J.-K. Lee, and K. D. Riew Anti-Apoptotic Effects of Caspase Inhibitors on Rat Intervertebral Disc Cells J. Bone Joint Surg. Am., April 1, 2006; 88(4): 771 - 779. [Abstract] [Full Text] [PDF]

				A. Ashare, M. M. Monick, L. S. Powers, T. Yarovinsky, and G. W. Hunninghake Severe Bacteremia Results in a Loss of Hepatic Bacterial Clearance Am. J. Respir. Crit. Care Med., March 15, 2006; 173(6): 644 - 652. [Abstract] [Full Text] [PDF]

				A. Kumar, A. Kumar, P. Michael, D. Brabant, A. M. Parissenti, C. V. Ramana, X. Xu, and J. E. Parrillo Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-{kappa}B and Induces Apoptosis in Human Cardiac Myocytes J. Biol. Chem., December 30, 2005; 280(52): 42619 - 42626. [Abstract] [Full Text] [PDF]

				F. M. Syed, H. S. Hahn, A. Odley, Y. Guo, J. G. Vallejo, R. A. Lynch, D. L. Mann, R. Bolli, and G. W. Dorn II Proapoptotic Effects of Caspase-1/Interleukin-Converting Enzyme Dominate in Myocardial Ischemia Circ. Res., May 27, 2005; 96(10): 1103 - 1109. [Abstract] [Full Text] [PDF]

				S. Lancel, O. Joulin, R. Favory, J. F. Goossens, J. Kluza, C. Chopin, P. Formstecher, P. Marchetti, and R. Neviere Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction Circulation, May 24, 2005; 111(20): 2596 - 2604. [Abstract] [Full Text] [PDF]

				C. Gras-Le Guen, A. Jarry, G. Vallette, C. Toquet, C. Colombeix, C. L. Laboisse, G. Potel, J-C. Roze, D. Bugnon, and T. Debillon Antibiotic therapy reduces nitrosative stress and programmed cell death in the rabbit foetal lung Eur. Respir. J., January 1, 2005; 25(1): 88 - 95. [Abstract] [Full Text] [PDF]

				K. A. Webster and N. H. Bishopric Apoptosis Inhibitors for Heart Disease Circulation, December 16, 2003; 108(24): 2954 - 2956. [Full Text] [PDF]

				J. Suzuki, E. Bayna, E. Dalle Molle, and W. Y. W. Lew Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats J. Am. Coll. Cardiol., February 5, 2003; 41(3): 482 - 488. [Abstract] [Full Text] [PDF]

				R. M Smith, S. Lecour, and M. N Sack Innate immunity and cardiac preconditioning: a putative intrinsic cardioprotective program Cardiovasc Res, August 15, 2002; 55(3): 474 - 482. [Abstract] [Full Text] [PDF]

				M. J. TOBIN Critical Care Medicine in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 565 - 583. [Full Text] [PDF]

				H. FAUVEL, P. MARCHETTI, G. OBERT, O. JOULAIN, C. CHOPIN, P. FORMSTECHER, and R. NEVIERE Protective Effects of Cyclosporin A from Endotoxin-induced Myocardial Dysfunction and Apoptosis in Rats Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 449 - 455. [Abstract] [Full Text] [PDF]

				H. Fauvel, P. Marchetti, C. Chopin, P. Formstecher, and R. Neviere Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1608 - H1614. [Abstract] [Full Text] [PDF]