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Crataegus special extract WS[R] 1442 prevents aging-related endothelial dysfunction.

ARTICLE INFO

Keywords:

Aging

Endothelial dysfunction

Crotaegus

Polyphenols

Endothelium-derived hyperpolarizing factor

Endothelium-derived nitric oxide

Endothelium-derived contracting factors

Oxidative stress

ABSTRACT

Aging is associated with a markedly increased incidence of cardiovascular diseases due, in part, to the development of vascular endothelial dysfunction. The present study has evaluated whether the Crataegus special extract WS[R] 1442 prevents the development of aging-related endothelial dysfunction in rats, and, if so, to determine the underlying mechanisms. Wistar rats received either a control diet or the same diet containing 100 or 300 mg/kg/day of WS[R] 1442 from week 25 until week 65. Vascular reactivity was assessed in mesenteric artery rings using organ chambers, oxidative stress by dihydroethidine staining and cyclooxygenase-1 (COX-1) and -2 (COX-2) expression by immunohistochemistry. Acetylcholine-induced endothelium-dependent relaxations in mesenteric artery rings were blunted in 65-week-old rats compared to 16-week-old rats. This effect was associated with a marked reduction of the endothelium-derived hyperpolarizing factor (EDHF) component whereas the nitric oxide (NO) component was not affected. Aging was also associated with the induction of endothelium-dependent contractile responses to acetylcholine. Both aging-related impairment of endothelium-dependent relaxations and the induction of endothelium-dependent contractile responses were improved by the Crataegus treatment and by COX inhibitors. An excessive vascular oxidative stress and an upregulation of COX-1 and COX-2 were observed in the mesenteric artery of old rats compared to young rats, and these effects were improved by the Crataegus treatment in conclusion, chronic intake of Crataegus prevented aging-related endothelial dysfunction by reducing the prostanoid-mediated contractile responses, most likely by improving the increased oxidative stress and the overexpression of COX-1 and COX-2.

[c] 2012 Elsevier GmbH. All rights reserved.

Introduction

Aging is associated with a markedly increased incidence of cardiovascular diseases due, in part, to the development of vascular endothelial dysfunction (Lakatta and Levy 2003). Indeed, the endothelium has a major role in the regulation of vascular homeostasis through the release of several potent relaxing and contracting factors. The endothelium-derived relaxing factors (EDRFs), which are predominant in healthy blood vessels and promote vascular protection, include nitric oxide (NO, Furchgott and Zawadzki 1980), endothelium-derived hyperpolarizing factor (EDHF, Chen et al. 1988) and prostacyclin (Moncada and Vane 1978). The endothelium-derived contracting factors (EDCFs), which appear frequently in diseased blood vessels, include endothelins, angiotensin II, cyclooxygenase-derived prostanoids and reactive oxygen species (ROS, Vanhoutte and Tang 2008). The unbalance between EDRFs and EDCFs subsequent to a reduced formation and/or increased degradation of EDRFs and/or to an over-production of EDCFs contributes to endothelial dysfunction, which accompanies major vascular diseases. Such an endothelial dysfunction is also observed during physiological aging, which is characterized by a progressive decrease in NO bioavailability (Imaoka et al. 1999), a reduced EDHF component (Goto et al. 2000) and often also an increased formation of EDCFs, in particularly, ROS (Hamilton et al. 2001) as well as cyclooxygenase-derived prostanoids (Vanhoutte and Tang 2008). Aging-related endothelial dysfunction has been observed in the human brachial artery (Celermajer et al. 1994), in the aorta (Kung and Luscher 1995) and the perfused mesenteric bed (Atkinson et al. 1994) of rats.

Chronic intake of polyphenol-rich food and beverages has been shown to improve endothelial function and to reduce the incidence of cardiovascular diseases (Michalska et al. 2010). Hawthorn extract (Crataegus ssp.) is a rich source of polyphenols, which has been shown to have cardiotonic and car-dioprotective properties. The Crataegus special extract WS[R] 1442 contains predominantly two major groups of polyphenolic compounds, a mixture of monomeric flavonoids and oligomeric procyanidins. Previous studies have shown that the Crataegus extract is a potent inducer of NO- and EDHF-mediated relaxations of coronary artery rings (Brixius et al. 2006). The aim of the present study was to determine whether chronic intake of the Crataegus extract is able to prevent the endothelial dysfunction occurring during aging, and if so, to investigate the underlying mechanisms.

Materials and methods

Crataegus special extract WS[R] 1442

Crataegus WS[R] 1442 is a special extract obtained from leaves with flowers of selected hawthorn species (Crataegus oxyacantha/Crataegus monogyna) by extraction with 45% (w/w) aqueous ethanol (drug/extract ratio 4-6.6:1). The extract is adjusted to a content of 17.3-20.1% oligomeric procyanidins.

In vivo treatment of rats

This study conforms to the Guide of Care and the Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 1996). Water was given ad libitum in a controlled environment (room temperature 21-22[degrees]C, room humidity 50 [+ or -] 5%). Male Wistar rats received either a control diet (9 rats) or the same diet containing either 100 (9 rats) or 300 mg/kg/day (9 rats) of the Crataegus special extract from week 25 until week 65. 16-Week-old rats (6 rats) were used as young control rats. Rats were anaesthetized with pentobarbital (50 mg/kg, intraperitoneally) and after excision, the mesenteric artery was placed in Krebs bicarbonate solution for the subsequent determination of vascular reactivity using organ chambers, immunohistochemistry and measurement of ROS.

Vascular reactivity studies

For the determination of changes in isometric tension, mesenteric artery rings were suspended in organ baths as described previously (Dal-Ros et al. 2011). Rings were contracted with 1 [micro]M of phenylephrine (PE) before the application of increasing concentrations of acetylcholine (Ach), sodium nitroprusside (an exogenous NO donor) or levcromakalim (an ATP-sensitive [K.sup.+] channel opener) to construct concentration-response curves. Sodium nitroprusside-and levcromakalim-induced relaxations were examined in endothelium-denuded rings of mesenteric arteries. In some experiments, rings were exposed to an inhibitor for 30 min before contraction with PE. The NO-mediated component of relaxation was determined in the presence of indomethacin (10 [micro]M) and charybdotoxin (100 nM) plus apamin (100 nM) to inhibit the formation of prostanoids and EDHF-mediated responses, respectively. The EDHF-mediated component of the relaxation was determined in the presence of indomethacin (10 [micro]M) and [N.sup.w]-nitrol-arginine (L-NA, 300 [micro]M) to inhibit the formation of prostanoids and NO, respectively. Endothelium-dependent contractions were assessed in the presence of L-NA to prevent the endothelial formation of NO, and charybdotoxin [K.sup.+] apamin to inhibit EDHF-mediated responses. Rings were contracted with PE (10-100 nM) to about 25% of the maximal contraction obtained by the Krebs bicarbonate solution containing a high [K.sup.+] concentration (80 mM). Thereafter increasing concentrations of ACh were added to the organ chamber.

The basal endothelial formation of NO was assessed indirectly by determining the endothelium-dependent depression of PE-induced contractile responses (Martin et al. 1986). For this purpose, contractions to increasing concentrations of PE were determined in endothelial-intact and endothelial-denuded rings of mesenteric artery.

Immunohistochemical determination of cyclooxygenase-1 and -2 expression in the mesenteric arterial wall

Segments of main mesenteric arteries were removed, embedded in OCT compound (Tissue-Tek, Sakura Finetek) and snap-frozen in liquid nitrogen. Frozen arteries were cryosectioned at 14 [micro]m. Sections were air-dried for 15 min and stored at -80[degrees]C until use. The slides were fixed with paraformaldehyde (4%), washed and treated with 10% milk containing 0.1% Triton-X 100 for 1 h at room temperature to block non-specific binding. The sections were then incubated overnight at 4[degrees]C with an antibody directed against COX-1 or -2 (1/200). Sections were then washed with PBS, incubated with the secondary antibody (Alexa 637-conjugated goat anti-rabbit) diluted (1/200) in the same buffer for 2 h at room temperature in the dark, and washed before being mounted in Vectashield (mounting medium for fluorescence, Vector Laboratories, Inc., Burlingame, CA 94010) and cover-slipped. For negative controls, primary antibodies were omitted.The samples were observed using a confocal laser-scanning microscope (Leica SP2 UV DM IRBE). Quantification of protein levels was performed using Image J 1.42q software (National Institutes of Health, USA).

Determination of vascular reactive oxygen species (ROS) formation

The oxidative fluorescent dye dihydroethidine was used to evaluate the in situ formation of ROS. Mesenteric arterial rings (3-4 mm length) were embedded in OCT compound (Tissue-Tek) and snap-frozen in liquid nitrogen. Frozen arteries were cryosectioned at 25 [micro]m. Sections were air-dried for 15 min and stored at -80 degrees]C until use. Dihydroethidine (2.5 [micro]M, Sigma) was applied onto unfixed cryosections of mesenteric arteries for 30 min at 37[degrees]C in a light-protected humidified chamber to determine the in situ formation of ROS. To determine the nature and the source of ROS, sections were incubated with either, superoxide dismutase (500 Mimi), MnTMPyP (membrane-permeant super-oxide dismutase mimetic, 100 [micro]M), polyethylene glycol-catalase (membrane-permeant analog of catalase, 500 Ul/m1), catalase (500 Ul/ml), L-NA (NO synthase inhibitor, 300 [micro]M), indomethacin (cyclooxygenase inhibitor, 10 ELM) for 30 min at 37[degrees]C before addition of dihydroethidine. Images were obtained with a confocal microscope and analyzed with Image J 1.42q software.

Materials

Antibodies were purchased as indicated: COX-1 monoclonal antibody, COX-2 polyclonal antibody (Cayman Chemical Company, Michigan, USA), 637 labeled goat anti-mouse IgG or 637 labeled goat anti-rabbit IgG (Invitrogen, Molecular Probes). Apamin and charybdotoxin were obtained from Latoxan (Valence, France). L-NA, indomethacin, ACh, PE, sodium nitroprusside, levcromakalim were obtained from Sigma-Aldrich.

Statistical analysis

Data are presented as mean [+ or -] S.E.M. of 11 different experiments. Mean values are compared using analysis of variance followed by Bonferroni post hoc test (comparison of selected pairs), using GraphPad Prism 5 (GraphPad Software, Inc., San Diego, CA, USA). The difference was considered to be significant when p value was less than 0.05.

Results

Crataegus treatment prevents the aging-related endothelial dysfunction in the mesenteric artery of 65-week-old rats

In mesenteric artery rings with endothelium, acetylcholine (Ach) caused concentration-dependent relaxations (Fig. 1A), which were significantly reduced in 65-week-old rats compared to young rats. The ACh-induced NO-mediated relaxations were similar in mesenteric artery rings from young rats and 65-week-old rats (Fig. 1C), whereas, the EDHF-mediated relaxations were markedly reduced in mesenteric artery rings of 65-week-old rats compared to I6-week-old rats (Fig. 1D). ACh was also able to evoke concentration-dependent contractile responses, which were significantly increased in 65-week-old rats compared to young rats (Fig. 1B). To determine whether aging is also related to an impaired basal formation of NO, the ability of the endothelium to depress contractile responses was evaluated. As expected, contractile responses to PE were slightly but significantly reduced in mesenteric artery rings with endothelium compared to those without endothelium in young control rats (Fig. 2A). In contrast to young rats, PE induced similar contractile responses in rings with and without endothelium of 65-week-old rats (Fig. 2B) indicating that the endothelium is no longer able to depress PE-induced contractile responses.

The chronic oral ingestion of either 100 or 300 mg/kg/day of the Crataegus extract from week 25 until week 65 significantly improved the aging-related blunted ACh-induced endothelium-dependent relaxations (Fig. 1A) and increased endothelium-dependent contractile responses (Fig. 1B), and restored also the ability of the endothelium to depress the PE-induced contractile responses (Fig. 2C and D). However, the Crataegus treatment did affect neither the NO nor the EDHF components (Fig. 1C and D). In addition, the Crataegus treatment did not affect relaxations evoked by either the exogenous donor of NO (sodium nitroprusside) or the ATP-sensitive [K.sup.+] channel opener (levcromakalim) in mesenteric artery rings without endothelium (Fig. 1E and F).

COX inhibitors and a TP receptor antagonist improve the aging-related endothelial dysfunction

The aging-related blunted ACh-induced endothelium-dependent relaxations were improved by treatment of rings with either the COX inhibitor (indomethacin), the COX-1 inhibitor (SC-560), the COX-2 inhibitor (NS-398) or the TP receptor antagonist (GR32191B) (Fig. 3A). In addition, indomethacin abolished the aging-related increased ACh-induced endothelium-dependent contractile responses (Fig. 3B).

Crataegus treatment prevents the aging-related increased vascular formation of ROS

ROS formation was markedly increased throughout the mesenteric arterial wall of 65-week-old rats compared to young rats. Chronic ingestion of 300 mg/kg/day of the Crataegus extract was associated with a significant reduced ROS level in the mesenteric arterial wall of 65-week-old rats, whereas a reduction was also observed with the dose of 100 mg/kg/day however this effect did not reach a statistically significant level (Fig. 4A). In order to determine the nature and sources of ROS, arterial sections from 65-week-old rats were treated with different inhibitors and the formation of ROS was assessed by fluorescence. The increased vascular ROS formation was markedly reduced by membrane-permeant analogs of superoxide dismutase (MnTMPyP) and catalase (PEG-catalase) but not by native superoxide dismutase and catalase indicating involvement predominantly of an intracellular formation of superoxide anions and hydrogen peroxide (Fig. 4B). It was also blunted by L-NA (an NO synthase inhibitor) and indomethacin demonstrating the involvement of uncoupled eNOS and cyclooxy-genases (Fig. 4B).

Crataegus treatment normalizes the aging-related vascular up-regulation of COX-1 and COX-2 expression

Since COXs are involved in the aging-related endothelial dysfunction and vascular oxidative stress, the vascular expression level of COX-1 and COX-2 was assessed by immunohistochemistry. The expression level of COX-1 and COX-2 was significantly increased throughout the arterial wall in mesenteric arteries from 65-week-old rats compared to young rats (Fig. 5). The chronic ingestion of 300 mg/kg/day of Crataegus extract normalized the expression of these proteins in mesenteric arteries of old rats to level similar as that seen in young rats, whereas the lower dose (100 mg/kg/day) reduced also COX-1 and COX-2 expression level but this effect did not reach significance (Fig. 5).

Discussion

The major findings of the present study is that chronic intake of the Craraegus special extract WS[R] 1442 from week 25 until week 65 prevented the aging-related blunted endothelium-dependent relaxations and the increased endothelium-dependent contractile responses in the mesenteric artery. The protective effect of the Crataegus extract most likely involves its ability to normalize the aging-related vascular oxidative stress and COX-1-and COX-2-mediated endothelium-dependent contractile responses.

Advancing age is a major risk factor for the development of cardiovascular diseases which is attributable, at least in part, to the development of vascular endothelial dysfunction (Seals et al. 2011). The present study indicates that ACh-induced endothelium-dependent relaxations are strongly reduced in the mesenteric artery of 65-week-old rats in comparison to young rats. These results are in line with several previous studies indicating that aging is associated with impaired endothelium-dependent relaxations as observed in various type of arteries such as the human brachial artery (Celermajer et al. 1994), the rat aorta (Kung and Luscher 1995), the rat carotid artery (Hongo et al. 1988) and the rat perfused mesenteric bed (Atkinson et al. 1994). In the rat mesenteric artery, endothelium-dependent relaxations to ACh involve mainly a NO component (Furchgott and Zawadzki 1980) and an EDHF component (Chen et al. 1988). Therefore, experiments have been performed to determine whether aging affects both components. The findings indicate that the ACh-induced EDHF-mediated relaxations are markedly reduced, whereas the NO-mediated relaxations are not affected. Endothelial dysfunction affecting predominantly the EDHF component with no or little effect on the NO component has also been observed previously in the mesenteric artery of hypertensive rats (Hilgers and Webb 2007), type 2 diabetic rats (Young et al. 2008) and aged rats (Goto et al. 2000). However, some studies have also observed that aging is associated with blunted NO-mediated relaxations, such as in the second and the third branch of the superior mesenteric artery (Matz et al. 2000), the aorta (van der Loo et al. 2000), the carotid artery (Hongo et al. 1988) and the coronary arteriole (Csiszar et al. 2002) of rats. In addition, experiments have been also performed to determine whether aging affects basal NO formation in the mesenteric artery as assessed indirectly by the ability of endothelial cells to depress contractile responses (Martin et al. 1986). Although phenylephrine-induced contractile responses are depressed in mesenteric artery rings with endothelium from young rats compared to those without endothelium, no such effect is observed in mesenteric artery rings from 65-week-old rats indicating that aging is associated with reduced basal NO formation.

The fact that endothelium-dependent relaxations in mesenteric artery rings of old rats were improved by indomethacin (a non-selective COX inhibitor), SC-560 (a selective COX 1 inhibitor), NS-398 (a selective COX 2 inhibitor) and by GR32191B (an antagonist of TP receptors) indicates that the endothelial dysfunction involves cyclooxygenase-derived prostanoids, which contract the vascular smooth muscle through activation of TP receptors, thereby counteracting endothelium-dependent relaxations. Similar observations have also been made in the aorta (Heymes et al. 2000) and the mesenteric artery (Matz et al. 2000) of old rats. These findings are in good agreement with the fact that pretreatment of rings with indomethacin abolished the aging-associated increased ACh-induced endothelium-dependent contractile responses.

Several studies have indicated that vascular oxidative stress plays a major role in aging-related endothelial dysfunction (Csiszar et al. 2002). In agreement with these data, the present findings indicate that oxidative stress was significantly increased in the arterial wall of 65-week-old rats compared to young rats, and involved an increased intracellular formation of superoxide anions and hydrogen peroxide. Since, the aging-related increased formation of ROS is reduced in the presence of inhibitors of either cyclooxygenases or eNOS, it implies the involvement of cyclooxygenases and uncoupled eNOS. COX-2 has also been involved in the excessive formation of ROS associated with the endothelial dysfunction in the mesenteric artery of a rat model of endotoxic shock (Actis-Goretta et al. 2006). The possibility that aging-related COX-mediated contractile responses and vascular oxidative stress are associated with changes in the vascular expression of COX-1 and COX-2 was evaluated by immunohistochemistry. Both the expression level of COX-1 and COX-2 were increased in 65-week-old rats compared to young rats. In addition, previous studies have indicated that oxidative stress plays a key role in the prostanoid-derived increased endothelium-dependent contractile responses in different cardiovascular diseases (Tian et al. 2011). Indeed, ROS have been suggested to activate endothelial COX-2 leading to the production PGF2[alpha], the most likely EDCF to be involved in the endothelial dys-function in renal arteries of renovascular hypertensive rats (Tian et al. 2011). Moreover, ROS have also been shown to activate COX-1 leading to the production of endoperoxides, which activate TP receptors, thereby accounting for endothelium-dependent contractile responses to ACh in the aorta of spontaneously hypertensive rats (Yang et al. 2002). Furthermore, angiotensin II caused a NADPH oxidase-mediated formation of ROS, which is able to stimulate COX-1 activity leading to the production of contracting prostanoids in small mesenteric arteries of mice (Virdis et al. 2007). Altogether, these findings indicate that oxidative stress activates cyclooxygenases, which, in turn, results in an increased formation of vasocontracting prostanoids but most likely also to an increased formation of ROS, which perpetuates the endothelial dysfunction. The present findings indicate that chronic ingestion of either 100 or 300 mg/kg/day of a Crataegus extract for 40 weeks prevented the aging-related blunted endothelium-dependent relaxations in rats. Previous studies have also shown that oral supplementation with polyphenol-rich sources improves endothelial function in various animal models of cardiovascular pathologies associated with endothelial dysfunction. Indeed, red wine poyphenols improved the endothelial function in L-NA-induced hypertension (Pechanova et al. 2004), angiotensin II-induced hypertension (Sarr et al. 2006) and in middle-aged rats (Dal-Ros et al. 2011). The characterization of the protective effect of the Crataegus treatment indicated that neither the ACh-induced NO-nor the EDHF-mediated relaxations were improved despite a consistent improvement of endothelium-dependent relaxations. The findings also indicate that the Crataegus treatment prevented the aging-related blunted basal endothelial formation of NO as assessed indirectly by the depression of the contractile responses at the dose of 300 mg/kg/day. In addition, the aging-related increased ACh-induced endothelium-dependent contractions are abolished by the Crataegus treatment. The beneficial effect of the Crataegus treatment on aging-related endothelium dependent contractile responses is most likely explained by the normalization of the vascular expression of COX-1 and COX-2 and vascular oxidative stress. Previous studies have also shown that 5-day oral treatment with Crataegus pinnatifida prevents inflammatory responses induced by lipopolysaccharide in rats, at least in part, through inhibition of the hepatic expression of COX-2, TNF-[alpha], IL-[beta], and IL-6 (Li and Wang 2011). Moreover, Crataegus oxycantha reduced myocardial oxidative stress in a model of ischemia-reperfusion injury (Swaminathan et al. 2010).

Conclusion

Aging is associated with the development of an endothelial dysfunction in the mesenteric artery of rats, which is most likely due to a reduced EDHF-mediated endothelium-dependent relaxation, reduced basal NO formation and the appearance of endothelium-derived contractile responses involving cyclooxygenase-derived prostanoids acting on TP receptors to contract the vascular smooth muscle. Chronic intake of the Crataegus extract effectively prevented the development of aging-related endothelial dysfunction as indicated by normalized endothelium-derived contractile responses and basal NO formation; these effects are most likely the consequences of a reduced expression of COX-1 and COX-2 and formation of ROS.

Conflict of interest

This work was supported, in part, by a research grant by Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany. The funders have participated in the study design and redaction of manuscript, but they did not contribute to data collection and analysis. No additional external funding was received for this study.

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N. Idris-Khodja (a), C. Auger (a), E. Koch (b), V.B. Schini-Kerth (a), *

(a.) CNRS UMR 7213. Faculty of Pharmacy, University of Strasbourg, Illkirch. France

(b.) Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany

* Corresponding author.

E-mail address: valerie.schini-kerth@unistra.fr (V.B. Schini-Kerth).

0944-7113/$--see front matter [c] 2012 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2012.04.005
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Author:Idris-Khodja, N.; Auger, C.; Koch, E.; Schini-Kerth, V.B.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUGE
Date:Jun 15, 2012
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