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Endocrinology Vol. 148, No. 10 4579-4584
Copyright © 2007 by The Endocrine Society

BRIEF COMMUNICATION

17ß-Estradiol Regulates Constitutive Nitric Oxide Synthase Expression Differentially in the Myocardium in Response to Pressure Overload

Xavier Loyer, Thibaud Damy, Zuzana Chvojkova, Estelle Robidel, Françoise Marotte, Patricia Oliviero, Christophe Heymes and Jane-Lise Samuel

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 689 Centre de Recherche Cardiovasculaire INSERM Lariboisiére (X.L., T.D., Z.C., E.R., F.M., P.O., C.H., J.-L.S.), Institut Fèdèratif de Recherche 139, Université D. Diderot (X.L., T.D., Z.C., E.R., F.M., P.O., C.H., J.-L.S.), and Assistance Publique-Hôpitaux de Paris Hôpital Lariboisière (T.D.), Cedex 10, 75475 Paris, France

Address all correspondence and requests for reprints to: Dr. Jane-Lise Samuel, Institut National de la Santé et de la Recherche Médicale Unité 689 Centre de Recherche Cardiovasculaire INSERM Lariboisière, 41, Boulevard de la Chapelle, Cedex 10, 75475 Paris, France. E-mail: samuel{at}larib.inserm.fr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estrogens [E(2)] exert direct and indirect effects that can modulate the development of cardiac disease. However, the precise mechanisms that are involved remain undefined. Our objective was to investigate whether E(2) affected the activity and expression of constitutive nitric oxide synthase (NOS) isoforms (NOS3 and NOS1) in cardiac hypertrophy induced by thoracic aortic constriction (TAC). Ovariectomized (Ovx) and nonovariectomized Wistar rats were subjected to TAC. Ovx animals received E(2) or placebo 3 wk after surgery for 11 wk. Afterward cardiac function and degree of left ventricular hypertrophy were assessed by echocardiography. NOS activity and expression were studied by biochemical techniques. TAC led to significant left ventricular hypertrophy (>90%) irrespective of hormonal status. Cardiac performance declined more in TAC+Ovx (–20%, P < 0.015) than in the two other TAC groups [TAC and TAC+Ovx+E(2)]. Total NOS activity decreased significantly in the Ovx groups. In response to TAC, total NOS activity increased whatever the E(2) status. Specific NOS3 activity dramatically decreased in the Ovx groups (–55%, P < 0.009) and was unaltered by TAC. By using coimmunoprecipitation assays, we showed that NOS3/caveolin-1 complexes negatively regulated NOS3 activity as a function of E(2) status. On the other hand, NOS1 expression and activity were markedly increased in hypertrophied myocardium (P < 0.003), irrespective of E(2) status. This study demonstrates a differential regulation of NOS expression and activity in response to pressure overload and E(2) status, the former being mainly involved in the induction of NOS1, whereas the latter regulated NOS3 activity and in turn cardiac function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE INCIDENCE OF cardiac diseases such as left ventricular hypertrophy (LVH) and heart failure differs significantly in women before and after menopause (1). In this context, it has been hypothesized that estrogen may play an important role in the pathogenesis of heart failure because postmenopausal women have increased risk of developing cardiac diseases in coincidence with a declining level of 17ß-estradiol (2). Recently estrogens have been shown to attenuate the development of pressure overload-induced hypertrophy in mice (3). However, the mechanisms by which estrogens modulate LVH development are still subject to debate.

One proposed mechanism involved in LVH and participating in the transition to heart failure is a decrease in nitric oxide (NO) bioavailability (4). NO is produced by different NO synthases (NOSs). Three isoforms have been identified: two constitutive (endothelial NOS, or NOS3, and neuronal NOS, or NOS1) and one inducible (NOS2). One of the major mechanisms regulating the activity of Ca-dependent NOS involves interactions with caveolins, the structural proteins of caveolae. Caveolin-1 interacts with NOS3 in endothelium, whereas caveolin-3 could interact with NOS1 in cardiomyocytes (5, 6). In the case of NOS3, the estrogen pathway has recently emerged as another mechanism able to regulate enzyme expression and activity, including at the level of microdomains such as caveolae (7).

All three NOS isoforms might be expressed within myocardium, depending on the pathophysiological status. In the failing heart of both humans and rats, myocardial NOS activity is maintained through a distinct regulation of constitutive NOS that includes an increase in NOS1 expression and activity together with a decrease in NOS3 expression and activity (6, 8). An increase in NOS1 has also been observed in the heart of hypertensive aged rats (9). Estrogens are able to regulate NOS1 expression and activity in neuronal tissues (10, 11), but their role in cardiac tissue remains undefined.

In the present study, we tested the hypothesis that the beneficial effects of 17ß-estradiol [E(2)] observed in humans and in experimental models (2, 12) involve estrogen modulation of cardiac NOS. Therefore, we investigated NOS activity as well as the respective parts of NOS1 and NOS3 activity in the heart of ovariectomized (Ovx) and nonovariectomized Wistar rats that had undergone transverse aortic constriction (TAC) or sham operation. Expression of NOS isoforms in the heart and their interactions with their respective allosteric regulators caveolin-1 and caveolin-3 were analyzed. Finally, the specific impact of E(2)supplementation on Ovx animals was analyzed.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and experimental protocol
All experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 85-23, revised 1996). A phytoestrogen-free diet (2014; Harlan, Gannat, France) was given to animals throughout the study.

Under anesthesia, TAC was performed in 25-d-old female Wistar rats (Iffa Credo, L’Arbresle, France), as previously described (13). Sham-operated animals (Sh) were submitted to a similar protocol. At the same time, Ovx was performed. Three weeks later, randomized Ovx animals in both Sh and TAC groups received an estrogen pellet (0.25 mg per 90-d release; Innovative Research of America, Sarasota, FL) [Ovx+ E(2)]. Animals were killed 14 wk after surgery. Uterine atrophy in Ovx animals was used to validate our model (P < 0.001) (Table 1Go) (study design in supplemental Fig. 1, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://endo.endojournals.org). Six groups were analyzed (13–21/group): Sh without ovariectomy, without TAC), TAC (without ovariectomy, TAC), Sham with ovariectomy (ShOvx), TAC with ovariectomy (TAC+Ovx). ShOvx and TAC+Ovx animal groups received estrogen supplementation [Sh+Ovx+E(2), TAC+Ovx+E(2)].


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  		TABLE 1. Anatomic, echocardiographic, and functional parameters in response to stenosis, ovariectomy, and estrogen supplementation

 
Echocardiographic, hemodynamic, and anatomical parameter measurement
Echocardiographic parameters were analyzed as described previously (8). Hemodynamic and anatomical parameters are described (supplemental Fig. 2 and the effects of ovariectomy), and TAC and supplementation on these different parameters are shown (supplemental Table 2 and supplemental Fig. 3).

NOS activity, immunoblotting, and coimmunoprecipitation assays
Left ventricular (LV) myocardial NOS activity was measured by the conversion of (3H)-L-arginine (NEN Life Science Products/DuPont, Les Ulis, France) to (3H)-L-citrulline. Western blots and coimmunoprecipitation were performed with specific antibodies against the different proteins NOS3, NOS2, NOS1, caveolin-1, and caveolin-3 as described (supplemental Figs. 3–5).

Statistical analysis
Results are expressed as mean ± SEM. Statistical analysis was performed using Statview 5.0 (SAS Institute, Cary, NC). ANOVA analysis followed by a Bonferroni-Dunn correction was performed. P < 0.015 was considered significant for multigroup comparison.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of estrogens on the development of LVH and cardiac function
TAC induced severe cardiac hypertrophy (>95%) in all the experimental groups whatever the parameter considered [posterior wall thickness (PWT), heart weight, LV weight, or LV weight to body weight ratio] (Table 1Go). No statistical difference was found as a function of estrogen status except for PWT, which was higher in TAC+Ovx than TAC animals (P = 0.0005). As also shown in Table 1Go, several parameters indicated that cardiac function declined in all TAC groups: the percentage of fractional shortening decreased and LV end diastolic pressure (LVEDP) increased (P < 0.004 and P < 0.0017, respectively, vs. matched sham groups). Interestingly, ovariectomy exacerbated the decline in cardiac function as underlined by the further decrease in fractional shortening (TAC vs. TAC+Ovx, P < 0.01, t test) (Table 1Go). E(2) supplementation reversed the process.

It is worth noting that neither TAC nor E(2) deprivation markedly affected LV diameters during both systole and diastole.

Respective effects of estrogen status and pressure overload on cardiac NOS activity
In the Ovx group in the absence of TAC, total NOS activity dramatically decreased, compared with nonovariectomized animals (P = 0.013). E(2) supplementation (P < 0.006 vs. Sh+Ovx) reversed this process. In response to TAC, total cardiac Ca2+-dependent NOS activity was enhanced (+43, +85, +40% vs. respective matched sham groups, P < 0.015) (Fig. 1Go), irrespective of estrogen status.


Figure 1
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  		FIG. 1. Respective effects of hypertrophy and estrogen status on total NOS activity in the heart. Activity of constitutive NOS isoforms in whole LV extracts; n = 4 per group. *, P = 0.007 vs. Sh; $, P = 0.012 vs. Sh; {dagger}, P < 0.0055 vs. TAC and TAC+Ovx+E(2 ); {ddagger}, P = 0.011 vs. Sh+Ovx; #, P = 0.011 vs. Sh+Ovx+E(2 ).

 
These results indicated that estrogens are necessary for the highest NOS activity and that pressure overload per se increased total NOS activity in the LV. To obtain a more precise definition of the respective pathways of estrogen and pressure overload in the control of NOS activity, we investigated the expression and activity of the two constitutive NOSs, i.e. NOS3 and NOS1, because NOS2 was undetectable (supplemental Fig. 2).

Changes in NOS3 expression and activity in the myocardium as a function of estrogen and hypertrophic status
Ovariectomy dramatically decreased NOS3 activity in myocardium (–55% Sh+Ovx vs. Sh P = 0.0083). E(2) supplementation totally corrected this decrease (P = 0.013 vs. Ovx groups) (Fig. 2AGo). In response to TAC, NOS3 activity did not vary significantly when compared with the respective sham groups (Fig. 2AGo) irrespective of estrogen status.


Figure 2
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  		FIG. 2. NOS3 activity and expression in LV extracts as a function of hypertrophic and hormonal status. A, Specific NOS3 activity; n = 4 per group. *, P < 0.005 vs. Sh. B, Representative NOS3 Western blotting and corresponding quantification of NOS3 expression. AU, Arbitrary unit. Equal loading of the gel was verified by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Ponceau S red; n = 9 per group. *, P = 0.009 vs. Sh; {dagger}, P = 0.007 vs. TAC; and {ddagger}, P = 0.0043 vs. TAC+Ovx.

 
At the protein level (Fig. 2BGo), the absence of estrogens did not alter NOS3 expression in Sh+Ovx hearts. In response to TAC, NOS3 increased by +50% (P < 0.01 vs. Sh). This increase was blunted in the TAC+Ovx group (TAC vs. TAC+Ovx, P = 0.007). E(2) supplementation restored the TAC-induced increase in NOS3 expression [Sh+Ovx+E(2) vs. TAC+Ovx+E(2); +82% P = 0.008].

To gain further insight into the mechanisms controlling NOS3 activity, we investigated the interactions between NOS3 and caveolin-1. Ovariectomy induced an increase (+227% vs. Sh, P < 0.0001) in NOS3/caveolin-1 complexes (Fig. 3AGo), which was corrected by E(2) supplementation. After TAC, the relative level of NOS3/caveolin-1 complexes was enhanced (+77%, P = 0.012 vs. Sh) (Fig. 3AGo). TAC when combined with Ovx did not affect the level of NOS3/caveolin-1 as observed in the Ovx groups. E(2) supplementation restored the TAC-induced increase in NOS3/caveolin-1 complexes.


Figure 3
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  		FIG. 3. Ovariectomy induced NOS3-caveolin-1 (Cav-1) interaction in rat heart in relation to specific NOS3 activity. A, Coimmunoprecipitation of NOS3 and caveolin-1 from whole LV extracts; n = 4 animals/group. IP, Immunoprecipitation; IB, immunoblotting. *, P < 0.015 vs. Sh; {dagger}, P < 0.001 vs. Sh; and {ddagger}, P < 0.015 vs. Sh+Ovx. B, Correlation between specific NOS3 activity and relative amount of NOS3 bound to caveolin-1.

 
Interestingly, it emerged that NOS3 activity was negatively correlated (R2 = 0.94) to the amount of NOS3/caveolin-1 complexes (Fig. 3BGo). These changes were unrelated to caveolin-1 expression, which was stable whatever the groups (supplemental Fig. 3, A and B). Finally, we verified using coimmunoprecipitation that NOS3 did not bind to caveolin-3 (data not shown).

It thus emerged that estrogens play a key role in the regulation of NOS3 activity through the control of NOS3/caveolin-1 complex formation.

Changes in NOS1 expression and activity in the myocardium as a function of estrogen and hypertrophic status
NOS1 activity was not altered by either Ovx or E(2) supplementation (Fig. 4AGo). In response to TAC, specific NOS1 activity increased 2- to 3-fold when compared with the matched sham groups (P < 0.002) (Fig. 4AGo). At the protein level (Fig. 4BGo), NOS1 expression was not influenced by Ovx and E(2) supplementation (Fig. 4BGo). However, in response to TAC, NOS1 expression increased dramatically. Differences were noted according to estrogen status [+90% TAC vs. Sh, P < 0.0001, +70% TAC+Ovx+E(2) vs. ShOvx+E(2), P = 0.0005; +50% TAC+Ovx vs. Sh+Ovx P < 0.013]. In fact, correlation analysis revealed that NOS1 activity was closely related to the level of NOS1 expression (R2 = 0.88) (Fig. 4CGo).


Figure 4
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  		FIG. 4. NOS1 activity and protein expression in LV extracts as a function of hypertrophic and hormonal status. A, Specific NOS1 activity; n = 4 per group. *, P < 0.001 vs. respective Sh. B, Representative Western blotting and corresponding quantification of NOS1 expression. AU, Arbitrary unit. Equal loading of the gel was verified by glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Ponceau S red; n = 9 per group. *, P < 0.001 vs. Sh; {dagger}, P < 0.015 vs. Sh+Ovx and P = 0.0059 vs. TAC; {ddagger}, P = 0.0005 vs. Sh+Ovx+E(2 ); #, P < 0.015 vs. TAC+Ovx. C, Correlation between NOS1 activity and protein expression in LV homogenates (R2 = 0.88).

 
To confirm that negative modulators such as caveolin-3 were not involved in the control of NOS1 activity, we verified that neither the amount of NOS1/caveolin-3 complexes nor the amount of free caveolin-3 in total caveolin-3 varied among the experimental groups (supplemental Fig. 4Go).

Thus, it emerged that NOS1 expression and activity are mainly regulated through pressure overload-dependent mechanisms.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study is the first demonstration of the specific impact of E(2) on NOS isoform expression and activity in rat heart and, in turn, on cardiac function. We have shown that estrogen deficiency primarily affected NOS3 activity through a mechanism involving protein-protein interaction (especially with caveolin-1). Furthermore, we demonstrate that pressure overload induced an up-regulation of NOS1 independently of E(2) status. These results highlight the distinct mechanisms that regulate the expression and activity of NOS3 and NOS1 in the heart in response to severe pressure overload.

Increased NOS activity in hypertrophied heart apparently contrasted with the decreased NO bioavailability classically described (see reviews in Refs. 5 and 14). In our model, the enhanced NOS activity in ventricles after TAC primarily reflected an increase in NOS1 activity.

The increase in NOS1 activity that we observed is related to the up-regulation of the enzyme in the rat heart in response to severe pressure overload. These results are in line with those obtained in skeletal muscle in which enhancement of NOS1 expression and activity has been associated with development of hypertrophy (15, 16). We provide further evidence indicating that NOS1 induction in hypertrophied myocardium is independent of both E(2) status and degree of cardiac dysfunction and did not counteract the NOS3 down-regulation as observed in congestive heart failure (6, 8). In addition, we show a closed relationship between NOS1 activity and expression level in the heart, as found in skeletal muscle (16). Furthermore, NOS1 activity appeared to be independent of the subcellular location of the enzyme, including caveolin-3 interactions. In fact, neither the level of NOS1/caveolin 3 complexes nor the level of caveolin-3 varied in hypertrophied heart, unlike the failing heart situation (8). The small changes in NOS1-caveolin-3 complexes after TAC, together with high NOS1 expression, might reflect abundant Ca2+-calmodulin-enzyme complexes (17) and/or NOS1 interaction with other Ca2+ transporters such as PMCA4b (18), SERCA, or RYR (19). Of note, the induced NOS1 expression in the heart after TAC could occur in both smooth muscle cells and cardiomyocytes, as already observed in hypertensive animals (20, 21).

One cannot exclude the possibility that the NOS1 splice variant expressed during cardiac hypertrophy and cardiac failure differed, as discussed elsewhere (18). These data thus emphasize the differential regulatory mechanisms involved in the up-regulation of NOS1 and/or in its subcellular location in response to severe pressure overload, myocardial infarction (8), or spontaneous hypertension and aging (9).

There is evidence that the estrogen receptor-{alpha} mediates the nongenomic activation of NOS 3 (review in Ref. 22). We showed that E(2) deficiency leads to a decrease in total cardiac NOS activity due to changes in NOS3 activity (23). Unlike some authors (23, 24) but in accordance with others (25, 26), we did not detect changes in NOS3 or NOS2 expression as a function of either E2 or pressure status. Such a difference in findings could be related to experimental design (age of animals, time of study after surgery). We provide evidence that the main mechanism by which E(2) regulates NOS3 activity in the heart involves interactions with caveolin-1, in agreement with other authors (5, 7), and not by caveolin-3 as already described (23). Thus, our in vivo data demonstrate that E(2) deficiency induces a unique increase in NOS3/caveolin-1 complexes, which in turn reflects inactive NOS3.

In response to TAC, ovariectomy in Wistar rats did not significantly influence the development of LVH, LV cavity size, or LVEDP (Table 1Go), in agreement with data obtained in a genetic model of hypertension (27, 28). Noticeably, E(2) supplementation failed to attenuate LVH, contrary to previous reports (3, 29). As pointed out by Leinwand (30), the variables of experimental studies may play a role in E(2)-related variations in cardiac responses to TAC. The age of the animals (juvenile vs. adult) is a major issue. A second and perhaps more important issue might be the time that E(2) treatment is started. An effect of the hormone on LVH was observed when supplementation preceded (3, 29) but not when it followed TAC surgery (this issue). This emphasized the preventive effect of E(2) on the development of LVH. The fractional shortening analysis showed that estrogen-deprived animals exhibited enhanced signs of cardiac dysfunction. E(2) supplementation improved cardiac function, thus confirming the beneficial effect of E(2) therapy on cardiac performance (31).

As proposed by Ichinose et al. (32) using NOS3–/– mice, the absence of NOS3 enhanced LV dysfunction in a similar model of TAC-induced pressure overload (32). However, in our models the decline in NOS3 activity must be related to the nongenomic effect of E(2) through interactions with caveolin-1, as already discussed. The fact that E(2) was required to evidence hypertrophy-induced changes in NOS3-caveolin-1 complexes validates this concept. As a result, E(2) signaling through the endothelial estrogen receptor could potentially contribute to E(2) differences in LV adaptation to pressure overload. In contrast, E(2) status did not alter NOS1 activity or expression in myocardium. Therefore, our data support the concept that NOS1 expression and activity in the heart are mainly regulated through mechanosensitive pathways independently of E(2) levels, as observed in skeletal muscle (15).

The respective functions of NOS1 and NOS3 and NOS1/3-derived NO were not addressed in the present study. It has been suggested that NOS3-derived NO, or exogenous NO, may be involved in preventing the development of cardiac hypertrophy. The data herein do not support this hypothesis. The beneficial effect of E(2) through maintenance of NOS3 activity would be the prevention endothelial dysfunction and in turn cardiac dysfunction (Table 1Go). With regard to NOS1, it has been proposed that the enzyme modulates calcium homeostasis and ß-adrenergic response (33). In addition, recent data (34, 35) indicate that NOS1 plays a trophic role at the onset of the hypertrophic process. Our results demonstrating active NOS1 in all hypertrophied myocardium are in line with a protrophic role of NOS1. Furthermore, we demonstrate that these effects are independent of E(2) status.

In summary, the present data demonstrate that E(2) mainly regulated NOS3 activity through protein-protein interactions, whereas pressure overload induced up-regulation of NOS1. These results support the recent concept concerning the importance of the source of NO in pathophysiological situations. Our findings may help to elucidate the molecular mechanism underlying the beneficial effects of estrogen on cardiac responses to severe pressure overload.


   Acknowledgments
 
We thank Dr. C. Delcayre, Dr. B. Swynghedauw, and Dr. Y. Sainte-Marie for their helpful discussion.


   Footnotes
 
The work was supported by Institut National de la Santé et de la Recherche Médicale, Groupe de Réflexion sur la Recherche Cardiovasculaire, Société Française d’Hypertension Artérielle, Association Française Contre les Myopathies, and Fondation de France. X.L. has a fellowship from the French Ministère de la Recherche et de l’Enseignement Supérieur.

Disclosures: X.L., T.D., Z.C., E.R., F.M., P.O., C.H., and J.-L.S. have nothing to disclose.

First Published Online August 2, 2007

Abbreviations: E(2 ), 17ß-Estradiol; LV, left ventricular; LVEDP, LV end diastolic pressure; LVH, LV hypertrophy; NO, nitric oxide; NOS, NO synthase; Ovx, ovariectomized; Sh, sham-operated; PWT, posterior wall thickness; TAC, thoracic aortic constriction.

Received February 16, 2007.

Accepted for publication July 26, 2007.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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