Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

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
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bondarenko Oleksandr
Graier Wolfgang
Malli Roland
Altmetrics:

Dimensions Citations:

Plum Analytics:
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)
Crataegus extract
Calcium
Endothelium
© Meduni Graz Impressum