The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway.
The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway.
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DOI：
10.1016/j.yjmcc.2012.07.002
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发表时间：
2012-10
影响因子：
5
通讯作者：
E. Willer;R. Malli;A. Bondarenko;S. Zahler;A. Vollmar;W. F. Graier;R. Fürst
中科院分区：
文献类型：
--
作者：
E. Willer;R. Malli;A. Bondarenko;S. Zahler;A. Vollmar;W. F. Graier;R. Fürst
WS® 1442已被证明是治疗轻度充血性心力衰竭的有效和安全的疗法。除此之外，我们最近还发现WS® 1442通过影响内皮钙信号传导，防止凝血酶诱导的血管屏障功能障碍和随后的水肿形成。本研究旨在分析WS® 1442对人内皮细胞内钙浓度[Ca 2 +] i的影响，并研究其潜在机制。使用比率钙测量和FRET传感器，我们发现WS® 1442通过耗尽内质网（ER）浓度依赖性地增加基础[Ca 2 +] i，并抑制随后组胺触发的[Ca 2 +]i升高。有趣的是，增加的[Ca 2 +] i既没有触发收缩机制的激活，也没有导致屏障破坏（大分子渗透性）。它也不损害内皮细胞活力。通过膜片钳记录评估，WS® 1442仅轻微影响内皮Na+/K+-ATP酶，但通过抑制肌质/内质网Ca 2 + ATP酶（SERCA）和激活肌醇1，4，5-三磷酸（IP 3）途径增加[Ca 2 +] i。最重要的是，WS® 1442不诱导钙库操作的钙内流（SOCE），但甚至不可逆地阻止组胺诱导的SOCE。综上所述，WS® 1442通过预先从ER释放无毒的Ca 2+来防止[Ca 2 +] i的有害的高渗透性相关的升高。WS® 1442干扰SERCA和IP 3途径，而不诱导SOCE。这种有趣机制的阐明有助于理解心血管药物WS® 1442的复杂药理学。
WS® 1442 has been proven as an effective and safe therapeutical to treat mild forms of congestive heart failure. Beyond this action, we have recently shown that WS® 1442 protects against thrombin-induced vascular barrier dysfunction and the subsequent edema formation by affecting endothelial calcium signaling. The aim of the study was to analyze the influence of WS® 1442 on intracellular calcium concentrations [Ca2+]iin the human endothelium and to investigate the underlying mechanisms. Using ratiometric calcium measurements and a FRET sensor, we found that WS® 1442 concentration-dependently increased basal [Ca2+]iby depletion of the endoplasmic reticulum (ER) and inhibited a subsequent histamine-triggered rise of [Ca2+]i. Interestingly, the augmented [Ca2+]idid neither trigger an activation of the contractile machinery nor led to a barrier breakdown (macromolecular permeability). It also did not impair endothelial cell viability. As assessed by patch clamp recordings, WS® 1442 did only slightly affect endothelial Na+/K+-ATPase, but increased [Ca2+]iby inhibiting the sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA) and by activating the inositol 1,4,5-trisphosphate (IP3) pathway. Most importantly, WS® 1442 did not induce store-operated calcium entry (SOCE), but even irreversibly prevented histamine-induced SOCE. Taken together, WS® 1442 prevented the deleterious hyperpermeability-associated rise of [Ca2+]iby a preceding, non-toxic release of Ca2+from the ER. WS® 1442 interfered with SERCA and the IP3pathway without inducing SOCE. The elucidation of this intriguing mechanism helps to understand the complex pharmacology of the cardiovascular drug WS® 1442.