CLINICAL STUDY: HEART FAILURE
Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol
Lothar Rössig, MD*,
Judith Haendeler, PhD*,
Ziad Mallat, MD ,
Benedicte Hugel, PhD ,
Jean-Marie Freyssinet, PhD,
Alain Tedgui, PhD,
Stefanie Dimmeler, PhD* and
Andreas M. Zeiher, MD*
* Division of Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany
INSERM U141, IFR "Circulation," Hôpital Lariboisiere, Paris, France
INSERM U143, Le Kremlin-Bicetre, Strasbourg, France
Manuscript received January 31, 2000;
revised manuscript received July 11, 2000,
accepted August 18, 2000.
Reprint requests and correspondence: Dr. Stefanie Dimmeler, Molecular Cardiology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Dimmeler{at}em.uni-frankfurt.de
OBJECTIVES
The purposes of this study were to determine whether the serum of patients with congestive heart failure (CHF) can induce apoptosis of endothelial cells and to elucidate the underlying mechanisms. Moreover, the effect of the beta-blocker carvedilol was investigated.
BACKGROUND
Congestive heart failure is associated with impaired endothelial function in the peripheral systemic vasculature and with systemic release of inflammatory cytokines. Pro-inflammatory cytokines have been shown to induce endothelial cell apoptosis in vitro. Therefore, we hypothesized that CHF is associated with enhanced apoptosis of endothelial cells.
METHODS
Human umbilical vein endothelial cells were exposed to the serum of patients with CHF (n = 15) or healthy volunteers (n = 11), and apoptosis was determined by fluorescence staining of the nuclei and demonstration of deoxyribonucleic acid laddering. Moreover, apoptotic membrane particles were detected in plasma samples of patients with CHF.
RESULTS
The serum of patients with CHF revealed a significantly enhanced pro-apoptotic activity as compared with age- and gender-matched healthy volunteers (p < 0.001). Furthermore, patients with CHF revealed significantly elevated plasma concentrations of apoptotic membrane particles. Apoptosis of endothelial cells correlated with elevated tumor necrosis factor-alpha (TNF-alpha) (r = 0.585, p = 0.002) and soluble TNF receptor serum levels (r = 0.517, p = 0.007). Carvedilol completely suppressed the increase in apoptosis induced by the serum of patients with CHF. Moreover, carvedilol dose-dependently inhibited TNF-alpha–induced apoptosis. The antiapoptotic activity of carvedilol was mediated by reduced activation of the caspase cascade through inhibition of mitochondrial cytochrome c release. The suppression of apoptosis by carvedilol was due to its antioxidative rather than beta-blocking effects, as the analogue BM91.0228, which has no beta-blocking activity, exerted similar effects.
CONCLUSIONS
These findings indicate that endothelial cell apoptosis may play a role in the pathophysiology of heart failure. Inhibition of endothelial cell apoptosis by carvedilol may contribute to the beneficial effects of carvedilol in patients with heart failure.
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Abbreviations and Acronyms
| | CHF | = congestive heart failure | | HUVECs | = human umbilical vein endothelial cells | | JNK | = c-JUN NH2-terminal kinase | | MAPK | = mitogen-activated protein kinase | | MTT | = 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide | | NYHA | = New York Heart Association | | sTNF-R1 | = soluble tumor necrosis factor–receptor 1 | | TBARS | = thiobarbituric acid reactive substances | | TNF-alpha | = tumor necrosis factor-alpha | | ZVAD-fmk | = Z-Val-Ala-Asp-fluoromethylketone |
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