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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Willer, EA; Malli, R; Bondarenko, AI; Zahler, S; Vollmar, AM; Graier, WF; Fürst, R.
The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway.
J Mol Cell Cardiol. 2012; 53(4):567-577
Doi: 10.1016/j.yjmcc.2012.07.002
Web of Science
PubMed
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FullText_MUG
- Co-authors Med Uni Graz
- Bondarenko Oleksandr
- Graier Wolfgang
- Malli Roland
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- Abstract:
- 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 [Ca(2+)](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 [Ca(2+)](i) by depletion of the endoplasmic reticulum (ER) and inhibited a subsequent histamine-triggered rise of [Ca(2+)](i). Interestingly, the augmented [Ca(2+)](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 [Ca(2+)](i) by inhibiting the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) and by activating the inositol 1,4,5-trisphosphate (IP(3)) 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 [Ca(2+)](i) by a preceding, non-toxic release of Ca(2+) from the ER. WS® 1442 interfered with SERCA and the IP(3) pathway without inducing SOCE. The elucidation of this intriguing mechanism helps to understand the complex pharmacology of the cardiovascular drug WS® 1442.
- Find related publications in this database (using NLM MeSH Indexing)
- Calcium - metabolism
- Calcium Channels - metabolism
- Calcium Signaling - drug effects
- Cells, Cultured -
- Endoplasmic Reticulum -
- Endothelial Cells - metabolism
- Flavonoids - pharmacology
- Human Umbilical Vein Endothelial Cells - metabolism
- Humans -
- Inositol 1,4,5-Trisphosphate Receptors - metabolism
- Patch-Clamp Techniques -
- Plant Extracts - pharmacology
- Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors
- Sodium-Potassium-Exchanging ATPase - metabolism
- Find related publications in this database (Keywords)
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- Calcium
- Endothelium