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Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol
L Rössig1, J Haendeler, Z Mallat
1Department of Internal Medicine IV, University of Frankfurt, Germany.
Insights
Congestive heart failure serum induces endothelial cell apoptosis, a process inhibited by carvedilol. This suggests carvedilol
Area of Science:
- Cardiovascular Medicine
- Cell Biology
- Pharmacology
Background:
- Congestive heart failure (CHF) is linked to poor endothelial function and systemic inflammation.
- Pro-inflammatory cytokines may drive endothelial cell apoptosis in CHF.
Purpose of the Study:
- To investigate if CHF serum induces endothelial cell apoptosis.
- To identify mechanisms behind this apoptosis.
- To assess carvedilol's effect on CHF-induced apoptosis.
Main Methods:
- Human umbilical vein endothelial cells were exposed to serum from CHF patients and healthy controls.
- Apoptosis was measured via nuclear staining and DNA laddering.
- Plasma apoptotic membrane particles were quantified.
Main Results:
- CHF serum significantly increased endothelial cell apoptosis compared to controls.
- Elevated plasma apoptotic membrane particles were observed in CHF patients.
- Apoptosis correlated with tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor levels.
- Carvedilol suppressed CHF-induced and TNF-alpha-induced apoptosis.
- Carvedilol's antiapoptotic effect involved inhibiting the caspase cascade and mitochondrial cytochrome c release, mediated by its antioxidative properties.
Conclusions:
- Endothelial cell apoptosis may contribute to heart failure pathophysiology.
- Carvedilol's inhibition of endothelial cell apoptosis could explain its therapeutic benefits in heart failure.
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.