کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2190643 1097806 2012 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway
چکیده انگلیسی

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 +]i in 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 +]i by depletion of the endoplasmic reticulum (ER) and inhibited a subsequent histamine-triggered rise of [Ca2 +]i. Interestingly, the augmented [Ca2 +]i did 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 +]i by 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 +]i by a preceding, non-toxic release of Ca2 + from the ER. WS® 1442 interfered with SERCA and the IP3 pathway without inducing SOCE. The elucidation of this intriguing mechanism helps to understand the complex pharmacology of the cardiovascular drug WS® 1442.


► WS® 1442 increases intracellular calcium concentrations in the human endothelium.
► This increase does not cause endothelial contraction, hyperpermeability or toxicity.
► WS® 1442 only slightly affects endothelial Na+/K+-ATPase.
► WS® 1442 blocks SERCA and activates the IP3 pathway.
► Moreover, WS® 1442 does not induce SOCE, but even inhibits histamine-evoked SOCE.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 53, Issue 4, October 2012, Pages 567–577
نویسندگان
, , , , , , ,