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Cardiovascular Research 2001 51(2):344-350; doi:10.1016/S0008-6363(01)00319-4
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Copyright © 2000, European Society of Cardiology

Prevention of endothelial dysfunction in heart failure by vitamin E

Attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression

Johann Bauersachsa,*, Ingrid Flemingb, Daniela Fraccarolloa, Rudi Busseb and Georg Ertla

aMedizinische Klinik der Julius-Maximilians-Universität Würzburg, Würzburg, Germany
bInstitut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany

* Corresponding author. Medizinische Universitätsklinik, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Tel.: +49-931-201-5301; fax: +49-931-201-5302 j.bauersachs{at}medizin.uni-wuerzburg.de

Received 7 November 2000; accepted 10 April 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: Enhanced vascular superoxide anion generation contributes to endothelial dysfunction in heart failure. However, the effect of long-term treatment with the antioxidant vitamin E is unknown. Methods and Results: Relaxant responses were determined in aortic rings from Wistar rats with heart failure 12 weeks after myocardial infarction (MI) and compared with responses in tissues from sham-operated animals. From the seventh post-operative day, rats were given either a standard chow or a chow enriched in vitamin E (approximate intake 100 mg/day). In rings from rats with heart failure, acetylcholine-induced relaxation was attenuated (maximum relaxation, Rmax 54±3%) when compared with rings from sham-operated animals (79±3%, n=12, P<0.01), while endothelium-independent relaxation elicited by sodium-nitroprusside was unchanged. Aortic superoxide generation was significantly enhanced in rats with heart failure. Vitamin E supplementation significantly improved acetylcholine-induced relaxation in rats with heart failure (Rmax 75±4%, P<0.01) and led to a leftward shift in sodium-nitroprusside-induced relaxation curve. Aortic expression of the β1-subunit of soluble guanylyl cyclase was significantly enhanced by vitamin E supplementation. In addition, the elevated vascular superoxide formation was normalised by vitamin E. Conclusions: These results demonstrate that dietary supplementation with the antioxidant vitamin E restores normal endothelial function, reduces vascular superoxide anion formation and increases the expression of the soluble guanylyl cyclase in rats with heart failure.

KEYWORDS Endothelial function; Free radicals; Heart failure; Vasoconstriction/dilation; Nitric oxide

This article is referred to in the Editorial by F. Visioli (pges 198–201) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
A reduced endothelium-dependent vasodilator capacity of the coronary and systemic circulations contributes to reduced myocardial perfusion, increased peripheral vascular resistance and elevated cardiac workload in patients with heart failure as well as in animal models of cardiac dysfunction [1–5]. Altered endothelial function has been attributed to a decreased production, and/or increased scavenging, of endothelium-derived nitric oxide (NO). An enhanced generation of superoxide (O2–) radicals may reduce the bioavailability of NO and contribute to the attenuation of endothelium-dependent dilation in heart failure [6]. Indeed, in patients with congestive heart failure oxidative stress is increased [7–9], and is reportedly related to exercise intolerance [10,11]. Vitamin E exerts beneficial effects on endothelial function in diabetes [12], hypercholesterolemia [13–16], hypercholesterolemic smokers [17] and in patients with spastic angina [18]. Furthermore, in patients with coronary artery disease, plasma {alpha}-tocopherol concentration is reported to favourably influence coronary endothelial function [19]. Taken together, these data may suggest an important role for vitamin E in facilitating NO-mediated relaxation. In rats with left ventricular hypertrophy, the transition to heart failure is reported to be prevented by vitamin E [20]. In addition, pre-treatment with vitamin E has been reported to reduce infarct size and to improve hemodynamics in several models of myocardial infarction (MI) [21–24]. However, the effect of long-term treatment with vitamin E on the endothelial dysfunction associated with chronic ischemic heart failure has not been elucidated. Therefore, in the present study, we investigated the effect of chronic (11 weeks) dietary vitamin E supplementation on endothelium-dependent and -independent relaxation in the aorta from rats with chronic heart failure after the experimental induction of MI.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.1 Study protocol, myocardial infarction, hemodynamic measurements
Left coronary artery ligations were performed in adult male Wistar rats (250–300 g) as previously described [25]. On the seventh postoperative day, rats were randomly allocated to standard rat chow or a vitamin E-enriched chow and received water ad libitum. The standard chow (R/M-H, SSNIFF Spezialdiäten, Soest, Germany) contained on average 100 mg/kg of {alpha}-tocopherol and this was supplemented with D,L-{alpha}-tocopherol to obtain a chow containing on average 10 g/kg of vitamin E [12]. The rats consumed approximately 10 g/day of chow, so that among the experimental diet groups, the calculated intake of vitamin E was 200 mg/kg body weight.

Hemodynamic studies were performed 12 weeks after coronary artery ligation under barbiturate anaesthesia and controlled respiration as described [25].

2.2 Sample collection, determination of infarct size and ventricular remodeling
After hemodynamic measurement, the heart was excised and dissected into atria, right, and left ventricle including septum. The left ventricle was the cut into three transverse sections: apex, middle ring (3 mm), and base. From the middle ring, 5-µm sections were cut at 100-µm intervals and stained with picrosirius red. The boundary lengths of the infarcted and non-infarcted endocardial and epicardial surfaces were traced with a planimeter digital image analyser. Infarct size (fraction of the infarcted left ventricle) was calculated as the average of all slices and expressed as the percentage of length of circumference and only rats with extensive infarcts (<40%) were included in the vascular reactivity study. Left ventricular dilatation index was calculated as left ventricular cavity area (area enclosed by left ventricular endocardial circumference) divided by body weight.

2.3 Vascular reactivity studies
The descending thoracic aorta was dissected following removal of the heart and cleaned of connective tissue. The upper section (10 mm) was immediately frozen in liquid nitrogen for Western blot analysis. The lower section (10 mm) was used for measurement of superoxide anion production, while the remainder was cut into rings (3 mm in length) and mounted in an organ bath (Föhr Medical Instruments, Seeheim, Germany) for isometric force measurement. The rings were equilibrated for 30 min under a resting tension of 2 g in oxygenated (95% O2; 5% CO2) Krebs–Henseleit solution (NaCl 118 mmol/l, KCl 4.7 mmol/l, MgSO4 1.2 mmol/l, CaCl2 1.6 mmol/l, K2HPO4 1.2 mmol/l, NaHCO3 25 mmol/l, glucose 12 mmol/l; pH 7.4, 37°C) containing the cyclo-oxygenase inhibitor diclofenac (1 µmol/l) [26]. Rings were repeatedly contracted with KCl (100 mmol/l) until reproducible responses were obtained. Thereafter, the rings were preconstricted with phenylephrine (0.3–1 µmol/l) to 80% of maximum constriction level and the relaxant response to the cumulative application of acetylcholine and sodium nitroprusside was assessed. In addition, the relaxant effect of exogenous superoxide dismutase (SOD, 600 U/ml) was determined. Furthermore, the acute effect of vitamin E on acetylcholine-induced relaxation in aortae from rats with heart failure was assessed by addition of vitamin E (10, 100 µmol/l, 30 min).

2.4 Measurement of superoxide anion formation
Vascular O2– formation was measured using lucigenin-enhanced chemiluminescence [26]. The light reaction between O2– and lucigenin (250 µmol/l) was detected in a luminometer (Wallac, Freiburg, Germany) during incubation of rings in a Hepes-modified Krebs buffer (pH 7.40). Signals were integrated over 30 s. and averages of the plateau phase were used for further calculation. The specific chemiluminescence-signal was expressed as counts per minute per mg dry weight of tissue (cpm/mg). Since lucigenin at a concentration of 250 µmol/l has been reported to increase vascular O2– formation by itself, a separate series of experiments was performed using a concentration of 5 µmol/l [27].

2.5 Western blot analysis
Aortic tissue was homogenized and protein extracted by alcoholic precipitation of the phenol phase obtained after the guanidinium-isothiocyanate/phenol/chloroform extraction method. These crude protein extracts (100 µg) were subjected to SDS–PAGE electrophoresis and transferred to nitrocellulose membranes. Proteins were detected using their specific antibodies and visualized by enhanced chemiluminescence.

2.6 Materials
All biochemicals were obtained from Sigma (Deisenhofen, Germany). Standard and vitamin E-enriched chow was obtained from SNIFF (Soest, Germany). The sGC β1 polyclonal antibody used was generated from the keyhole limpet hemocyanin-conjugated peptide sequences RNYGPEVWEDIKKEC, respectively, by EUROGENTEC (Seraing, Belgium).

2.7 Statistics
Relaxation responses were given as percentage relaxation relative to the preconstriction level. Values are expressed as mean±S.E.M. of n experiments with segments from different animals. Statistical analysis was performed by two-way analysis of variance (ANOVA) followed by a Bonferroni t-test or by the two-tailed Student's t-test for unpaired data, where appropriate, with P values <0.05 considered statistically significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Global parameters
Global parameters of rats with heart failure and sham-operated animals are shown in Table 1. Infarct size was similar in placebo (standard chow)- and vitamin E-treated animals. Left ventricular systolic and mean arterial pressure and dP/dtmax were significantly lower in both groups of rats with heart failure, whereas left ventricular end-diastolic pressure was markedly elevated. Long-term dietary supplementation with vitamin E slightly but not significantly reduced left ventricular end-diastolic pressure and left ventricular dilatation index and improved dP/dtmax.


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  		Table 1 Global parameters in rats with heart failure 12 weeks after myocardial infarction as compared to sham-operated animals (Sham)

 
3.2 Vasodilator responses in aortic rings
In phenylephrine-preconstricted aortic rings, acetylcholine induced a concentration-dependent relaxation which was blunted in aortae from rats with heart failure (Fig. 1 and Table 2). Chronic supplementation with vitamin E had no effect on responses of aortic rings from sham-operated animals, but completely restored the acetylcholine-induced relaxation of aortic rings from rats with heart failure (Fig. 1 and Table 2). In the placebo group, the concentration–relaxation curve to sodium nitroprusside was not different between sham-operated animals and rats with heart failure (Fig. 2 and Table 2). However, vitamin E supplementation induced a significant leftward shift in the concentration–relaxation curve to sodium nitroprusside in rats with heart failure, which was also apparent in sham-operated animals, although this effect was not statistically significant.


Figure 1
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  		Fig. 1 Relaxations induced by acetylcholine in phenylephrine-preconstricted aortic rings from rats with heart failure 12 weeks after myocardial infarction (bullet, {blacktriangledown}), as compared to sham-operated animals ({circ}, {bigtriangledown}). Animals were either treated with placebo (bullet, {circ}), or with vitamin E ({blacktriangledown}, {bigtriangledown}). Results are expressed as the mean±S.E.M. from 10 to 12 separate experiments. **P<0.01 Plac Infarct versus Plac sham, Vit. E sham, Vit. E Infarct.

 

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  		Table 2 Acetylcholine (Ach)- and sodium nitroprusside (SNP)-induced relaxations in phenylephrine-preconstricted aortic rings from rats with heart failure 12 weeks after myocardial infarction as compared to sham-operated animals (Sham)

 

Figure 2
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  		Fig. 2 Relaxations induced by sodium nitroprusside in phenylephrine-preconstricted aortic rings from rats with heart failure 12 weeks after myocardial infarction (bullet, {blacktriangledown}), as compared to sham-operated animals ({circ}, {bigtriangledown}). Animals were either treated with placebo (bullet, {circ}), or with vitamin E ({blacktriangledown}, {bigtriangledown}). Results are expressed as the mean±S.E.M. from 10 to 12 separate experiments. *P<0.05 Vit. E Infarct versus Plac Infarct and Plac sham.

 
Acute incubation of aortae from rats with heart failure with vitamin E (10, 100 µmol/l, 30 min) was without effect on acetylcholine-induced relaxation (Fig. 3).


Figure 3
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  		Fig. 3 Relaxations induced by acetylcholine in phenylephrine-preconstricted aortic rings from rats with heart failure 12 weeks after myocardial infarction ({circ}, bullet) either in the presence of vehicle ({circ}) or in the presence of vitamin E (100 µmol/l, bullet). Results are expressed as the mean±S.E.M. from six separate experiments.

 
Exogenous superoxide dismutase (SOD, 600 U/ml) elicited a dilator response, which was significantly enhanced in aortae from rats with heart failure (75±4 vs. 61±3%, P<0.05) indicating that vascular O2– production was markedly increased. Dietary supplementation with vitamin E significantly attenuated the SOD-induced relaxation (63±2%, P<0.05) in rats with heart failure.

3.3 Production of superoxide anions
O2– generation was greater in aortae from rats with chronic MI than the sham-operated group (Fig. 4) and was almost normalised in rats given vitamin E. Similar results were obtained using lucigenin at a concentration of 5 µmol/l (Sham: 86±18 cpm/mg, Placebo Infarct: 172±29 cpm/mg, vitamin E Infarct: 98±16 cpm/mg, P<0.05 Placebo Infarct versus Sham, vitamin E Infarct).


Figure 4
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  		Fig. 4 Superoxide anion production in aortic rings from rats with heart failure 12 weeks after myocardial infarction as compared to sham-operated animals. Rats were either treated with placebo or with vitamin E. Results are expressed as the mean±S.E.M. from eight to 10 separate experiments. *P<0.05 Plac Infarct versus Plac sham, Vit. E sham, Vit. E Infarct.

 
3.4 Expression of soluble guanylyl cyclase in rat aorta
As relaxations induced by sodium nitroprusside, which are mediated by activation of sGC, were increased by vitamin E supplementation, the sGC expression was analysed by Western blotting. Vitamin E supplementation enhanced the expression of the β1-subunit of the sGC in sham-operated rats, an effect which was even more pronounced in rats with heart failure (Fig. 5).


Figure 5
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  		Fig. 5 Western blot and statistical analysis showing vitamin E-induced alterations in the expression of the β1-subunit of the soluble guanylyl cyclase (sGC) in aortae from rats with heart failure 12 weeks after myocardial infarction as compared to sham-operated animals. Animals were either treated with placebo or with vitamin E.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
In the present study, we demonstrate that chronic vitamin E supplementation improves NO-mediated relaxations in rats with heart failure after MI, via a mechanism associated with a reduction in vascular superoxide anion production and an increase in the expression of sGC.

Antioxidants such as vitamin E have been shown to delay the progression of atherosclerosis (for review see Ref. [16]), and the Cambridge Heart Antioxidant Study (CHAOS) found that vitamin E markedly reduced the occurrence of MI, and all cardiovascular events in patients with coronary artery disease [28]. The beneficial effect of vitamin E supplementation has however been questioned, since vitamin E was reported to have no beneficial effect on clinical outcome (myocardial infarction, stroke, or death from cardiovascular causes) in patients after myocardial infarction (GISSI study [29]) or in patients at high risk for coronary events (history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor, HOPE study) [30]. However, heart failure patients were specifically excluded from these investigations and studies designed specifically to elucidate any effects of vitamin E supplementation on clinical outcomes in patients with heart failure are lacking.

There is a certain amount of evidence suggesting that vitamin E may exert a beneficial effect in heart failure. Indeed, in an experimental model of pressure overload, oxidative stress is reported to contribute to the transition from hypertrophy to heart failure, a response which is delayed by vitamin E supplementation [20]. A lack of local vitamin E tissue incorporation may also contribute to the development of heart failure. For example in rats after experimental MI, the concentration of vitamin E in the left ventricle and liver was found to be reduced despite the fact that plasma levels of the antioxidant were normal. In the same study, beginning vitamin E treatment prior to coronary ligation was associated with an improvement in hemodynamics 16 weeks after MI [21]. It is unclear, however, whether such effects can be attributed to a protective action of vitamin E on left ventricular remodeling after MI, or merely to a reduction of MI size. The latter possibility was suggested on the basis of studies in rats and pigs, in which pretreatment with vitamin E resulted in a reduction in infarct size [22–24]. In the present study, vitamin E supplementation slightly but non-significantly reduced left ventricular dilatation and left ventricular preload and improved dP/dtmax. MI size was not different between the experimental groups and vitamin E supplementation was initiated on the seventh post-operative day, specifically to exclude any effect of treatment on MI size.

Vascular reactivity, assessed as the acetylcholine-induced relaxation of aortic rings was attenuated after the induction of heart failure and was correlated with a significant increase in the vascular production of reactive oxygen species. Indeed, in tissue removed from rats with heart failure and fed a normal diet, the exogenous application of SOD elicited a marked relaxation of aortic rings, thus highlighting the crucial role played by superoxide anions in determining the tissue bioavailability of NO and confirming the results of our previous study [6]. The attenuated relaxant response to acetylcholine was completely normalised by dietary vitamin E supplementation. Although we did not directly evaluate NO production or eNOS expression, vitamin E appeared to normalise NO bioavailability since, as previously reported [6] the acetylcholine-induced relaxation in the rat aorta is mediated entirely by NO. In addition, in the present study, the elevated production of reactive oxygen species was restored to normal and the relaxation elicited by exogenous SOD in aortic rings from rats with heart failure was significantly smaller in animals fed a vitamin E-supplemented diet.

Preservation of endothelium-dependent relaxation by vitamin E has been observed in other pathophysiological states associated with increased oxidative stress, and chronic vitamin E supplementation is reported to improve endothelial function in diabetic rats [12], as well as in hypercholesterolemic rabbits [13,14]. High doses of vitamin E may, however, worsen endothelial function in cholesterol-fed animals due to pro-oxidant effects in LDL [31,32]. Interestingly, as in the present study, the long-term treatment of animals in vivo, rather than short-term exposure to the antioxidant in vitro, was required to prevent endothelial dysfunction elicited by oxidised LDL [15]. Such observations suggest that the incorporation of vitamin E over a prolonged period is necessary to actively protect the vasculature against the negative consequences of oxidative stress. Apart from its direct antioxidant effects, other actions of vitamin E may contribute to its positive action on the vasculature, one such action is the vitamin E-induced inhibition of protein kinase C stimulation [15,16,33].

In the present study, we found an additional mechanism, which may explain the pronounced improvement of vasodilator function in heart failure by vitamin E supplementation, that is, the marked increase in the expression of the β1-subunit of sGC. This key enzyme generates large amounts of cyclic GMP following its activation by endothelium-derived NO. The importance of alterations in the expression of sGC in vascular smooth muscle cells to the manifestation of ‘endothelial dysfunction’ is now recognized as one potential cause of reduced dilator responsiveness in aged spontaneously hypertensive rats [26,34]. It is, however, dangerous to make general statements about the importance of sGC expression in maintaining normal vascular function as the sequelae of cardiovascular disease in patients and the various animal models of hypertension, atherosclerosis and heart failure is complex. For example, in rats with chronic MI, we observed an increase in sGC expression despite a decrease in endothelium-dependent, NO-mediated relaxation [6]. In the present study, however, we did not observe an increase in sGC expression in rats with heart failure compared to sham-operated animals (both fed a normal diet). This discrepancy may be related to the fact that vascular reactivity and sGC expression were investigated at different times after the induction of MI (12 vs. 8 weeks), and it is well-known that in different models of endothelial dysfunction there is a time-dependent variability of vascular reactivity and of the expression of enzymes involved in NO-mediated relaxation [26,35,36]. Vitamin E supplementation, however, markedly enhanced sGC expression in rats with heart failure, resulting in enhanced sensitivity to the sGC activating compound, sodium nitroprusside. Since sGC-activity is highly sensitive to O2– [37], the beneficial effect of vitamin E is probably the result of a combination of at least two effects; an increase in sGC expression and a concomitant reduction in vascular O2– generation.

The improvement of endothelial vasodilator function associated with long-term dietary supplementation with vitamin E in heart failure may have considerable clinical relevance. Although vitamin E treatment for 3 months did not enhance the acetylcholine-induced increase in forearm blood flow in men after MI [38], beneficial effects of vitamin E on endothelial function have been documented in patients with spastic angina [18] and in hypercholesterolemic smokers [17]. The effects of vitamin E in patients with heart failure have yet to be closely investigated, but high doses of the antioxidant vitamin C are known to acutely improve endothelial function [39], thus suggesting that antioxidants may increase the vascular bioavailability of NO in these patients. The impact of restoring endothelial function, i.e., correcting endothelial dysfunction, in patients with heart failure has been highlighted by the recent finding that improved endothelial function results in an enhanced exercise capacity [40]. Thus we envisage that the correction of endothelial dysfunction by chronic vitamin E supplementation may help to improve quality of life and prognosis in patients with heart failure.

In conclusion, our data suggest that chronic dietary supplementation with vitamin E normalizes acetylcholine-induced relaxations by a combination of mechanisms; (1) increasing the bioavailability of NO by reducing O2– generation, (2) increasing sGC expression and (3) increasing sGC activity by alleviating of the inhibitory influence of an enhanced vascular generation of O2–. Assuming that the alterations observed in conductance vessels such as the aorta, also occur in the coronary and peripheral circulations vitamin E may prove to be an attractive additional therapeutic option for patients with heart failure.

Time for primary review 29 days.


   Acknowledgements
 
The authors wish to thank Claudia Liebetrau and Anna Dembny for expert technical assistance. This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB 355, B 10).


   Notes
 
{star} Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, GA, USA, November 7–10, 1999, and published in abstract form (Circulation 100, Suppl I, 1999, I-757).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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