Crataegus Special Extract WS 1442 Causes Endothelium-dependent Relaxation via a Redox-sensitive Src- and Akt-dependent Activation of Endothelial NO Synthase but Not via Activation of Estrogen Receptors

Département de Pharmacologie et Physico-Chimie, UMR 7175, Université Louis Pasteur de Strasbourg, Strasbourg, France.
Journal of cardiovascular pharmacology (Impact Factor: 2.14). 03/2009; 53(3):253-60. DOI: 10.1097/FJC.0b013e31819ccfc9
Source: PubMed


This study determined whether the Crataegus (Hawthorn species) special extract WS 1442 stimulates the endothelial formation of nitric oxide (NO), a vasoprotective factor, and characterized the underlying mechanism.
Vascular reactivity was assessed in porcine coronary artery rings, reactive oxygen species (ROS) formation in artery sections by microscopy, and phosphorylation of Akt and endothelial NO synthase (eNOS) in endothelial cells by Western blot analysis. WS 1442 caused endothelium-dependent relaxations in coronary artery rings, which were reduced by N-nitro-L-arginine (a competitive inhibitor of NO synthase) and by charybdotoxin plus apamin (two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses). Relaxations to WS 1442 were inhibited by intracellular ROS scavengers and inhibitors of Src and PI3-kinase, but not by an estrogen receptor antagonist. WS 1442 stimulated the endothelial formation of ROS in artery sections, and a redox-sensitive phosphorylation of Akt and eNOS in endothelial cells.
WS 1442 induced endothelium-dependent NO-mediated relaxations of coronary artery rings through the redox-sensitive Src/PI3-kinase/Akt-dependent phosphorylation of eNOS.

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Available from: Stéphanie Dal-Ros, Nov 26, 2014
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    • "Besides some few studies dealing with the effects on cardiomyocytes [5] [6], WS® 1442 has been found to affect the vascular endothelium by increasing NO production [7] [8]. The endothelium is perceived as a multifunctional disseminated organ that plays a crucial role in various physiological as well as pathological processes, such as the regulation of the vascular tone, host defense, or angiogenesis [9]. "
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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.
    Journal of Molecular and Cellular Cardiology 07/2012; 53(4):567-77. DOI:10.1016/j.yjmcc.2012.07.002 · 4.66 Impact Factor
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    • "NO-synthesis [3]. In contrast to the effect of an increase in plasma sodium, WS 1442 increases endothelial NO-synthase activity [17], [18]. At the same time PNa+ of the ESL decreases as shown in the present study. "
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    ABSTRACT: The endothelial glycocalyx (eGC) plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL) which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force-epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp.) extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i) the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii) WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic.
    PLoS ONE 01/2012; 7(1):e29972. DOI:10.1371/journal.pone.0029972 · 3.23 Impact Factor
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    • "The data suggested that AKT was implicated in the pro-angiogenic effect of AME. AKT-GSK3 signaling regulated vessel growth independent from the AKT-eNOS regulatory axis which promoted endothelium-dependent relaxation in a redox-sensitive manner (Kim et al. 2002; Anselm et al. 2009). To the best of our knowledge , little is known about the role of GSK3 signaling in the cardiovascular system. "
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    ABSTRACT: Astragalus membranaceus extract (AME) is a widely used herbal product for the treatment of cardiovascular diseases in China. The present study aimed to evaluate the cardiac protective effects of AME, and to probe the underlying molecular mechanism related to angiogenesis. In this study, AME with 75 microg/mL significantly increased proliferation, migration and tube formation on human umbilical vein endothelial cells (HUVECs). Moreover, in vivo experiments on rats with ligation of left anterior descending artery were performed to study the cardiac protective and angiogenic effect of AME (50 and 100 mg/kg i.g. for 3, 7, 14 days). The results showed that AME inhibited cardiac fibrosis, reduced infarct size, and increased capillary and arteriole densities. Meanwhile, western blot was used to determine protein levels of VEGF, p-AKT, p-GSK3beta and p-mTOR. AME significantly elevated protein expression of VEGF and increased phosphorylation of AKT, GSK3beta and mTOR. In conclusion, AME exerted cardiac protective and angiogenic effects in the ischemic injured heart. The activation of AKT/GSK3beta and AKT/mTOR pathways and elevated expression of VEGF may contribute to the promoted neovascularisation by AME.
    Pharmazie 02/2011; 66(2):144-50. DOI:10.1691/ph.2011.0738 · 1.05 Impact Factor
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