Increased Mortality and Aggravation of Heart Failure in Estrogen Receptor-β Knockout Mice After Myocardial Infarction

Pelzer, Theo; Arias-Loza, Paula; Hu, Kai; Bayer, Barbara; Dienesch, Charlotte; Calvillo, Laura; Couse, John F.; Korach, Kenneth S.; Neyses, Ludwig; Ertl, Georg

doi:10.1161/01.cir.0000159262.18512.46

Cited by 122 publications

(101 citation statements)

References 47 publications

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“…33 Systemic deletion of ER increased the mortality of myocardial infarction. 34 In the present study, we investigated the expression of cardioprotective substances such as ANP, BNP and HSP70 at the end of IMO stress for 30 min, and found that there was an upregulation of ANP and HSP70 mRNA but not BNP mRNA in OVX + E compared with OVX. In fact, the expression of ANP, BNP and HSP70 mRNA was also increased in response to IMO stress.…”

Section: Discussionmentioning

confidence: 86%

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Chronic Estrogen Supplementation Following Ovariectomy Improves the Emotional Stress-Induced Cardiovascular Responses by Indirect Action on the Nervous System and by Direct Action on the Heart

Umemura

Ishikura

Matsuda

et al. 2007

Circ J

156

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he incidence of cardiovascular diseases is low in pre-menopausal women, whereas it is increased in post-menopausal women. Estrogen supplementation therapy prevented the increase of cardiovascular diseases in post-menopausal women, 1 while recent metaanalysis of randomized trials showed no significant merits. 2 Effects of estrogen on cardiovascular diseases were attributed principally to the modification of serum lipid concentration and coagulation pathways, while direct actions of estrogen on the cardiovascular system contributed substantially to the cardiovascular protective effects of estrogen because estrogen receptors (ER and ER ) are expressed in the blood vessels and in the heart. 3,4 Both ER and ER are also widely expressed in the central nervous system. 5 Estrogen plays crucial roles in sexual behavior, learning and memory processes, protection against ischemic insults and modulation of autonomic nervous function. 6 In fact, a reduction of estrogen levels following menopause might increase the vulnerability of women to stress while estrogen supplementation attenuates the exaggerated response to stress or to increased sympathoadrenal activity. 7 A unique form of acute cardiac attack called "takotsubo cardiomyopathy", or "transient left ventricular apical ballooning" similarly occurs predominantly in postmenopausal women in association with emotional or physical stress. [8][9][10][11][12][13][14] Although the etiology of this syndrome is yet to be clarified, an increase of serum norepinephrine, epinephrine and neuropeptide Y levels at the onset of takotsubo cardiomyopathy compared with acute myocardial infarction suggests that the exaggerated sympathoadrenal activation triggered by stress is the primary cause of this cardiomyopathy. 9,10 Immobilization stress (IMO) in the rat provides an excellent animal model of emotional stress, which activates the hypothalamic-pituitary-adrenocortical system and the sympathoadrenal system. 15 We have succeeded in developing a model of this clinical condition in rats. [16][17][18][19][20] The characteristic changes such as elevation of Circ J 2007; 71: 565 -573 (Received September 19, 2006; revised manuscript received January 9, 2007; accepted January 23, 2007 Background Takotsubo cardiomyopathy is triggered by emotional or physical stress especially in postmenopausal women. A reduction in estrogen levels following menopause might underlie the high incidence of takotsubo cardiomyopathy. Methods and ResultsThe left ventricular contraction between ovariectomized rats (OVX) and OVX with estrogen supplementation (OVX + E) while subjected to immobilization stress (IMO) was compared. The IMO in combination with general anesthesia impaired the left ventricular contraction in both OVX and OVX + E. Estrogen supplementation tended to improve the IMO-induced cardiac dysfunction and significantly attenuated the increase of blood pressure and heart rate. To understand the protective mechanism of estrogen, the expression of c-fos mRNA, a marker of cellular activation was compared. ...

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Section: Discussionmentioning

confidence: 86%

“…The protective effects of estrogen in the heart have been demonstrated in several pathological conditions such as ischemia-reperfusion injury 33,34 and pressure-overload hypertrophy. 35 The ER -selective agonist but not the ERselective agonist reduced the infarct size of an ovariectomized rabbit heart.…”

Section: Discussionmentioning

confidence: 99%

Chronic Estrogen Supplementation Following Ovariectomy Improves the Emotional Stress-Induced Cardiovascular Responses by Indirect Action on the Nervous System and by Direct Action on the Heart

Umemura

Ishikura

Matsuda

et al. 2007

Circ J

156

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“…61,62 It appears, however, that ER␤ mediates the sex difference in response to pressure overload 63 and attenuates the transition to heart failure. 64 Female ER␤-null mice show a more rapid development of CHF and increased mortality rate after MI. 64 Although similar studies in mice that lack aromatase (the enzyme that converts testosterone to estradiol) have not been performed, increasing evidence indicates that treatment with an aromatase inhibitor leads to significant cardiovascular risk.…”

Section: Estrogen Receptors and The Heartmentioning

confidence: 99%

“…64 Female ER␤-null mice show a more rapid development of CHF and increased mortality rate after MI. 64 Although similar studies in mice that lack aromatase (the enzyme that converts testosterone to estradiol) have not been performed, increasing evidence indicates that treatment with an aromatase inhibitor leads to significant cardiovascular risk. 65 Estrogen can also initiate cellular changes through nongenomic mechanisms.…”

Section: Estrogen Receptors and The Heartmentioning

confidence: 99%

The Effects of Biological Sex and Diet on the Development of Heart Failure

Konhilas

Leinwand

2007

Circulation

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“…LV preload was assessed by end-diastolic pressure (LVEDP, mm Hg), contractility by ϩdP/dt max (mm Hg/sec) and (ϩdP/dt max )/IP which is the peak rate of rise in ventricular pressure normalized to instantaneous developed pressure and relaxation by -dP/dt max (mm Hg/sec); the time constant of isovolumic relaxation (, ms) was also determined. 16 Dobutamine was administered IV using a jugular vein. …”

mentioning

confidence: 99%

Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

Burkard

Rokita

Kaufmann

et al. 2007

Circulation Research

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Abstract-The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS Ϫ/Ϫ mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca 2ϩ -channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (nϭ12; PϽ0.01). Measuring of total NOS activity by conversion of [3 H]-L-arginine to [ 3 H]-L-citrulline showed a 30% increase in nNOS overexpressing mice (nϭ18; PϽ0.05). After a 2 week induction, nNOS overexpression mice showed reduced myocardial contractility. In vivo examinations of the nNOS overexpressing mice revealed a 17Ϯ3% decrease of ϩdp/dt max compared with noninduced mice (PϽ0.05). Likewise, ejection fraction was reduced significantly (42% versus 65%; nϭ15; PϽ0.05). Interestingly, coimmunoprecipitation experiments indicated interaction of nNOS with SR Ca 2ϩ ATPase and additionally with L-type Ca 2ϩ -channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes, I Ca,L density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca 2ϩ -transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca 2ϩ -channels and in turn reduces Ca 2ϩ -transients which accounts for the negative inotropic effect. (Circ Res. 2007;100:e32-e44.) Key Words: nNOS Ⅲ contractility Ⅲ excitation Ⅲ contraction coupling Ⅲ conditional overexpression S everal studies have demonstrated neuronal NO synthase (nNOS) protein expression within cardiac myocytes. 1 Specifically, nNOS has been localized to the sarcolemma 2,3 and the sarcoplasmatic reticulum (SR), 4 where it has been shown to be in close proximity to the SR Ca 2ϩ -release channel (RyR2) 5 and the SR Ca 2ϩ ATPase. However, the impact of nNOS on myocardial contractility remains largely controversial. Results from nNOS Ϫ/Ϫ mice and from pharmacological inhibition of nNOS provided insights into the role of nNOS in the cardiovascular system. But these approaches suffer from complete nNOS blockade and did not take into account a possible translocation of nNOS to specific subcellular sites. Some authors have shown, that inhibition of nNOS activity, via gene disruption or by pharmacological inhibition, enhanced basal contractility. 7,8 In the latter study, the positive inotropic effects of nNOS inhibition or gene disruption were related to ...

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Increased Mortality and Aggravation of Heart Failure in Estrogen Receptor-β Knockout Mice After Myocardial Infarction

Cited by 122 publications

References 47 publications

Chronic Estrogen Supplementation Following Ovariectomy Improves the Emotional Stress-Induced Cardiovascular Responses by Indirect Action on the Nervous System and by Direct Action on the Heart

Chronic Estrogen Supplementation Following Ovariectomy Improves the Emotional Stress-Induced Cardiovascular Responses by Indirect Action on the Nervous System and by Direct Action on the Heart

The Effects of Biological Sex and Diet on the Development of Heart Failure

Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

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