Rössig L, Haendeler J, Mallat Z, Hugel B, Freyssinet J M, Tedgui A, Dimmeler S, Zeiher A M
Department of Internal Medicine IV, University of Frankfurt, Germany.
J Am Coll Cardiol. 2000 Dec;36(7):2081-9. doi: 10.1016/s0735-1097(00)01002-0.
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.
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.
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.
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.
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.
本研究旨在确定充血性心力衰竭（CHF）患者的血清是否能诱导内皮细胞凋亡，并阐明其潜在机制。此外，还研究了β受体阻滞剂卡维地洛的作用。
充血性心力衰竭与外周体循环血管内皮功能受损以及炎症细胞因子的全身释放有关。促炎细胞因子已被证明在体外可诱导内皮细胞凋亡。因此，我们假设CHF与内皮细胞凋亡增加有关。
将人脐静脉内皮细胞暴露于CHF患者（n = 15）或健康志愿者（n = 11）的血清中，通过细胞核荧光染色和脱氧核糖核酸梯状条带的显示来确定细胞凋亡。此外，还检测了CHF患者血浆样本中的凋亡膜颗粒。
与年龄和性别匹配的健康志愿者相比，CHF患者的血清显示出明显增强的促凋亡活性（p < 0.001）。此外，CHF患者的血浆中凋亡膜颗粒浓度显著升高。内皮细胞凋亡与肿瘤坏死因子-α（TNF-α）升高（r = 0.585，p = 0.002）和可溶性TNF受体血清水平升高（r = 0.517，p = 0.007）相关。卡维地洛完全抑制了CHF患者血清诱导的凋亡增加。此外，卡维地洛剂量依赖性地抑制TNF-α诱导的凋亡。卡维地洛的抗凋亡活性是通过抑制线粒体细胞色素c释放从而减少半胱天冬酶级联反应的激活来介导的。卡维地洛对凋亡的抑制作用是由于其抗氧化作用而非β受体阻滞作用，因为无β受体阻滞活性的类似物BM91.0228也发挥了类似作用。
这些发现表明内皮细胞凋亡可能在心力衰竭的病理生理过程中起作用。卡维地洛抑制内皮细胞凋亡可能有助于其对心力衰竭患者的有益作用。
