雌激素的心脏保护作用_与_1_肾上腺素受体的相互作用及其信号通路_英文_

雌激素的心脏保护作用_与_1_肾上腺素受体的相互作用及其信号通路_英文_ Acta Physiologica Sinica, October 25, 2007, 59 (5): 571-577 571 Cardioprotection by the female sex hormone –– interaction with the β-adrenoceptor and its signaling pathways 1 *****Kathie A WONG, Yan MA, Wing-Tim CHENG, Tak-Ming WONG Department of Physiology, the University of Hong Kong, Hong Kong, China Abstract: Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of β-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/β-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down -regulation of the β - 1adrenoceptor. Th ere is also eviden ce th at estrogen su ppresses the expression an d activity of protein kinase A (P KA), a second messenger of the Gprotein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile fun ction. There is also s 2+preliminary evidence that estrogen may suppress the activity of Ca/calmodulin kinase II δc isoform (CaMKII-δc), another down- stream second messenger of the β -adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration 12+ of estrogen at physiological level could inhibit myocardial β-adren oceptor an d attenuate Cainflux independent of the estrogen 1 receptor. In addition, brain studies also show estrogen inhibits the activities activated by the β -adrenoceptor in brain regions respon- sible for the regu lation of arterial blood pressu re. Th us, it can be appreciated th at the in teraction between estrogen and the β - 1adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection. 2+Key words: estrogen; β -adrenoceptor; Ca/calmodulin kinase II; protein kinase A; cardioprotection; apoptosis 1 雌激素的心脏保护作用 —— 与 β - 肾上腺素受体的相互作用及其信号通路 1 *****黄心璇,马 妍,郑永添,黄德明 香港大学医学院生理学系，香港 摘 要:雌激素是女性体内主要的类固醇性激素。对于心肌缺血性伤害，切除卵巢的成年雌性大鼠在 β - 肾上腺素受体激动时，比正常雌性大鼠呈现更严重的心肌损伤;而去卵巢后的雌激素替补组大鼠对 β - 肾上腺素受体激动时心肌缺血性伤害的反 应则又回复到正常雌性大鼠水平，这为雌激素对抗缺血性伤害的心脏保护作用提供了证据。雌激素的这种保护作用是通过下 调 β - 肾上腺素受体的达来实现的。也有研究，雌激素能抑制蛋白激酶 A (protein kinase A, PKA) 的表达和活性，PKA 1是 G蛋白 / 腺苷酸环化酶 (adenylyl cyclase, AC)/cAMP/PKA 通路的第二信使，而该通路最终影响心肌的收缩功能。有初步证 s 2+据表明雌激素还能抑制 β - 肾上腺素受体通路下游的另一种第二信使 钙调蛋白激酶 II-δc (Ca/calmodulin kinase II-δc, CaMKII-δc) 1的活性，而 CaMKII-δc 参与 PKA 非依赖性的细胞凋亡。即时给予生理浓度雌激素可不通过雌激素受体而直接抑制心肌 β - 肾 12+ 上腺素受体并减弱 Ca内流。此外，脑研究也显示雌激素能抑制负责调节动脉血压脑区的 β - 肾上腺素受体活性。 因此，雌 1激素和 β - 肾上腺素受体之间的相互作用及其信号通路十分复杂。 雌激素不仅主导性别决定，在机体其它功能例如心脏保护 1 方面也具有重要作用。 关键词:雌激素;β - 肾上腺素受体;钙调蛋白激酶 II ;蛋白激酶 A ;心脏保护;凋亡 1 中图分类号:R331 . 3 ;Q2 5 7 Received 2007-09-03 Accepted 2007-09-20 This work was supported by ICST Holding (Ltd.), Hong Kong, the Research Grants Council, Hong Kong and Committee for Research and Conference Grants, the University of Hong Kong. **Contribute equally to this work. *Corresponding author. Tel: +86-852-28199194; Fax: +86-852-28559730; E-mail: wongtakm@hkucc.hku.hk 2+ increase in myocyte contraction and Catransient during 1 Introduction sustained β-adrenoceptor stimulation cannot be amelio- 1Prior to menopause, women have a significantly lower car- rated by the inhibition of the PKA pathway but CaMKII [7]diovascular risk compared to men, a disparity that has inhibition does. The cell apoptosis has also been shown [8]caused much controversy and debate and is believed to be to occur independent of PKA activity. attributed in part to the beneficial actions of the female sex The sympathetic influence on the heart varies in response hormone, estrogen. The favorable effects include its ac- to external stimuli. For example, during myocardial [1,2]tions on lipid profile and vasculature, including the pre- infarction, the sympathetic discharge is markedly increased vention of atherosclerotic plaque formation and prolifera- with a release of norepinephrine 100-1 000 times of nor- [3][9,10]tion of smooth muscle cells in arterial walls. Recently, mal values. This surge of norepinephrine increases the there has been increasing interest regarding the direct role contractility mainly via the β-adrenoceptor, leading to 1of estrogen in the heart, particularly at physiological con- marked increases in oxygen consumption, which exacer- centrations found in the body. Estrogen has been demon- bates the extent of the myocardial injury. Furthermore, the strated to down-regulate the β-adrenoceptor, the predomi- 1surge of norepinephrine increases apoptosis via the β- 1nant β-adrenoceptor in the heart responsible for the regu- adrenoceptor and CAMKII pathways and hence cell lation of cardiac contractility and heart rate. This article apoptosis. This detrimental effect of β-adrenoceptor acti- 1focuses on the evidence regarding the role of estrogen in vation during an acute insult had been demonstrated in iso- cardioprotection, in particular the interaction between the lated heart perfusion models where infarct size was sig- female hormone and the β-adrenoceptor and its signaling 1nificantly greater in hearts infused with isoprenaline, a β- [11]pathways. adrenoceptor agonist, than that without infusion. 2 β-adrenoceptora ctivation in the heart 13 Estrogen inhibits the effects of β-adrenoceptor The β-adrenoceptor is activated by the sympathetic ner- stimulation via the estrogen receptor (ER) 1 vous system, one of the most important extrinsic mecha- It has been reported that isoprenaline affects the heart rate nisms regulating cardiac function. During an acute insult, of female rats to different extents depending on the phase a surge of norepinephrine is released from the sympathetic [12] of the oestrous cycle . This has led to the belief that es- nerve terminal and activates α- and β-adrenoceptor sub- trogen plays a role in cardiovascular regulation by affect- types in the heart. There are two dominant β subtypes, β1 ing the β-adrenoceptor in the heart. In an isolated heart [4]and β, which are both expressed in the heart. β- 21perfusion model, there was no significant difference in in- adrenoceptor stimulation in particular has a role in con- farct size between OVX rats and sham rats in the absence tractility and relaxation, heart rate and cell apoptosis. This of β-adrenoceptor stimulation. When the hearts were occurs via two pathways. The primary pathway is the treated with isoproterenol, a non-selective β-adrenoceptor well established Gprotein/adenylyl cyclase (AC)/cAMP/ s agonist, the sham rats had significantly smaller infarct size protein kinase A (PKA) pathway, activation of which has as well as reduced heart rate and developed pressure com- 2+ 4 main effects: an increase of Cainflux via the L-type 2+ 2+ pared to OVX rats. Replacement of estrogen for 6 weeks Cachannel, release of Cafrom the sarcoplasmic reticu- restored the estrogen level to that of the normal female rats lum (SR) via the ryanodine receptor (RyR), re-uptake of 2+ 2+ 2+ and subsequently restored the infarct size to that of the Caby the CaATPase (SERCA) and extrusion of Ca[13]+2+ [5]sham controls. This observation indicates that estrogen of the cell via the Na-Caexchanger (NCX). This in protects the heart against injury induced by β-adrenoceptor turn enhances cardiac contractility and relaxation, and hence stimulation. increases oxygen consumption. Inhibition of PKA attenuates The effect of 17β-estradiol is ER-mediated as evidenced the increase in myocyte contraction mediated by short- by the lack of changes in the left ventricular developed term β-adrenoceptor stimulation. The second pathway is 1-8 2+pressure (LVDP) in the presence of 1×10mol/L ICI182,780, the Ca/calmodulin kinase II (CaMKII) pathway, activa- a selective ER antagonist. OVX mice had a poorer reco- tion of which leads to cell apoptosis and enhancement of 2+ very of LVDP following ischemia and reperfusion in the the L-type Cachannel, RyR, SERCA and NCX activity. presence of β-adrenoceptor stimulation with isoprenaline. CaMKII is responsible for the cardiac contractile dysfunc- [6]When OVX mice were treated with an ER-β-selective agonist tion from excessive β-adrenoceptor stimulation. The 1 Kathie A WONG et al: β-Adrenoceptor and its Signaling Pathways in Cardioprotection by Female Sex Hormone 573 1 [2,3-bis(4-hydroxyphenyl)-proprionite, DPN] for 2 weeks were significantly elevated in OVX rat, and the effects was [12,18]at 0.1 mg/kg per day, their recovery improved significantly . restored to the normal level by estrogen replacement[14]superseding that of the controls. This suggests that estrogen may suppress the expression of PKA, thus suppressing its activity. cAMP increased the PKA activity in rat hearts in all three groups. Interestingly, 4 Estrogen down-regulates the β-adrenoceptor 1 the increase in cAMP in response to PKA was the same in In 2003, Thawornkaiwong and co-workers demonstrated all three groups of rats, indicating that although the PKA an up-regulation of β-adrenoceptor and protein expres- 1expression and activity were suppressed by the female sex [15]sion in the heart of OVX rats. A subsequent study fur- [12]hormone, its responsiveness to cAMP was not affected. ther showed that estrogen replacement restored the ex- So the female sex hormone suppresses not only the β - 1 [11]pression of the receptor back to normal. Furthermore, adrenoceptor, but also PKA, one of its downstream second the study showed that incubation of ventricular myocytes messengers. -9 from OVX rats for at least 24 h with 1×10mol/L 17β- The basal activities of PKA effectors were also enhanced estradiol down-regulated the β-adrenoceptor and was ac- 1in OVX rat heart, an effect reversed by estrogen replacement. companied by a reduction of injury in response to ischemic 2+ [12]These effectors including the L-type Cachannel, RyR, -7 insult in the presence of 1×10mol/L isoprenaline. In 2+ which release Ca from the SR, and NCX, which ex- contrast, when myocytes from OVX rats were incubated 2+ trudes Ca from the cytoplasm after excitation contrac- with estrogen for 12 h, there was no effect on the expres- [18]tion coupling. Blockade of PKA with selective inhibitor sion of β-adrenoceptor and the injury in response to is- 1[12,18]also reversed the effects of ovariectomy. This provides chemic insult in the presence of isoprenaline. This obser- evidence that estrogen suppresses the PKA activity, thus vation supported the notion that cadioprotective effects of suppressing the activities of these effectors, which are re- estrogen is dependent on the down-regulation of the β- 12+ sponsible for altered Cahomeostasis. Ovariectomy has [15]adrenoceptor by the female hormone. been shown to reduce the ratio of SERCA, responsible for 2+ the re-uptake of Caback to the SR to phospholamban 5 Acute administration of estrogen at physiological (PLB), which inhibits SERCA activity. This effect was [19,20]concentrations inhibits the effects of isoprenaline reversible with estrogen replacement. There were also [18,19] [20] studies demonstrating either no changeor an increase0.1-1 nmol/L 17β-estradiol, which itself has no effect, re- in the expression of SERCA after ovariectomy. Results for duced the heart rate and the developed pressure in the [19,20]PLB have been similar. There is insofar no evidence -7 isolated perfused rat heart treated with 1×10mol/L iso- on the relationship between PKA and SERCA/PLB after [16]2+ 2+ prenaline. It also inhibited Cainflux via the L-type Ca ovariectomy. [16,17] [16] channeland cAMP contentin ventricular myocytes 2+ The alterations in Cahandling at these sites can be re- treated with isoprenaline. The effects were not affected by 2+ 2+flected by the intracellular Ca([Ca]) transients induced [16]i100 nmol/L tamoxifen, a selective ER antagonist. This by electrical stimulation and caffeine. The electrically in- suggests an interaction between estrogen and either β- 12+2+duced [Ca]transient (E[Ca]) is triggered by an electri- i iadrenoceptor or molecules downstream of its signaling cal stimulation, which mimics the depolarization of the sar- pathway, i.e., cAMP. Unlike the interaction following colemmal membrane by the arrival of an action potential. chronic treatment with estrogen, which involves the ER, 2+ This subsequently opens the L-type Cachannel and al- acute administration of estrogen does not involve the clas- 2+lows the entry of extracellular Ca, which triggers the sical ER. 2+ 2+release of more Cavia the RyR on the SR by a Ca- 2+[5]2+induced Ca-release mechanism. The resultant [Ca]i 6 Estrogen suppresses PKA transient triggers muscle contraction. It was shown that 2+When the expression of the protein messengers within the the amplitude of the E[Ca]was increased in OVX rats i G/AC/cAMP/PKA pathway in OVX rat hearts was com- and this effect was restored to normal by estrogen re- s[18]pared to those of the normal sham rats, it was found that placement for 6 weeks. This provides evidence to sup- the expression of the Gand Gas well as cAMP content port the notion that estrogen suppresses the activities of αs i3 2+ both L-type Cachannel and RyR. On the other hand, the was the same in hearts of female rats with and without [12]2+ovaries. On the other hand, the PKA level and its activity decay of the E[Ca] was reduced after ovariectomy, again i [18]an effect which was reversed by estrogen replacement, stimulation is most likely the CaMKII, well known to play 2+ handling in the heart. Preliminary a regulatory role in Casupporting that estrogen also suppresses the removal of 2+Ca. Interestingly, the SERCA activity was not altered by study in our laboratory showed that in the hearts from ovariectomy, indicating that estrogen does not affect the OVX rats, the expression and phosphorylation of CaMKII- 2+ Cahandling by SERCA, which is responsible for re- δc, one of the CaMKII isoforms, were elevated following 2+ uptake of over 90% of the cytosolic Caafter excitation- ovariectomy and restored to normal by estrogen replace- contraction (E-C) coupling. The alterations in the caffeine- ment (Ma, Cheng and Wong unpublished results). CaMKII- 2+2+induced [Ca]transient (C[Ca]) should provide evidence δc is a common intermediary in the stimuli-induced cell i i2+[8]to explain the observation. The C[Ca]opens up RyRs, apoptosis pathway in the heart. It is likely that estrogen i 2+ suppresses CAMKII-δc thus protecting the heart during thereby increasing the surge of Cafrom the SR into the [21,22]2+an ischemic insult. Further studies are warranted. cell. The amplitude of the C[Ca]indicates the amount i 2+ of releasable Cain the SR while the decay represents the 2+ rate of removal of Cavia the NCX. It was found that the 8 Interaction between estrogen and the β - 1 2+amplitude of the C[Ca]was increased while the decay i adrenoceptor in the brain was reduced following ovariectomy, indicating that the 2+ 2+ A recent study reported that in OVX rats, administration of amount of Careleased from the SR and removal of Ca isoprenaline induced hypotension and the effect was at- via the NCX were increased. When the relative proportions 2+ tenuated by subcutaneous administration of 17β-estradiol of Caremoval from cytoplasm by the SERCA and NCX benzoate (EB) at 10 µg/0.1 mL for 2 d, suggesting that were compared, it was found that after ovariectomy, the 2+ estrogen inhibits the hypotensive actions of β-adrenoceptor proportion of Caremoval via the NCX was increased 1[24]stimulation. Further study showed that isoprenaline en- from 6.9% to 23.3%, which was also restored to normal hanced the Fos-IR expression, an indication of neuronal by estrogen replacement, indicating that the enhanced ac- activation, in nuclei in the baroreflex, namely, nucleus tractus tivity of the NCX contributed significantly to the extrusion 2+ solitarius (NTX), postrema (AP), rostral ventrolateral me- of Cain OVX rats. This is necessary in view of the in- 2+ dulla (RVLM) and lateral parabrachial nucleus (LPBN). EB creased Caentry into the cell. So estrogen suppresses suppressed the enhanced Fos-IR expression in the AP and the basal activity of PKA, which in turn suppresses the 2+ LPBN by isoprenaline, indicating that the female sex hor- activities of its effectors, the L-type Cachannel, RyR, 2+ mone inhibited the stimulatory action of isoprenaline at these and NCX, resulting in reductions in Caup-take via the L- 2+ 2+ two nuclei, resulting in attenuated hypotension. Unfortunately, type Cachannel, release of Cafrom the SR and re- 2+ moval of Cavia the NCX. It is likely that estrogen also whether this phenomenon is mediated via the ER is not yet reduces the SERCA/PLB, thus reducing the re-uptake of known. 2+ Cavia the SERCA to SR. The suppressive actions of estrogen, which may be due 9 Other actions of the female sex hormone 2+ mainly to a reduction of basal PKA activity, on Caho- In addition to down-regulation of the β-adrenoceptor and 1meostasis result in reduced contractile functions. Indeed it suppression of PKA, estrogen also has other direct effects has been shown that the extent of myocyte shortening on the heart. It has been shown that estrogen directly an- was significantly greater, while the duration of shortening 2+ [25,26]tagonizes the L-type Cachannel activity. In estrogen- and decay were significantly shorter, in ventricular deficient mice, there is an increased expression of L-type myocytes from OVX rats than that in the sham control 2+ [27][19,23]Cachannel. Also, ovariectomy has been shown to in- female rats. This was accompanied by a larger ampli- 2+ [28] 2+crease the Ca sensitivity of the myofilaments . Estrogen tude and shorter decay time of the [Ca]transient in the i [29]replacement restores the response to normal. The re- ventricular myocytes from OVX rats than that from the 2+ [19,23]duction in Casensitivity may contribute to the reduction sham female rats. These effects were reversed by es- in contractile function and oxygen consumption during trogen replacement. ischemia. It has been shown that incubation of H9c2 cells derived 7 Estrogen down-regulates CaMKII from the heart with 100 nmol/L 17β-estradiol for 24 h [30]increased the expression and activity of Kchannel. The PKA-independent pathway responsible for the increase ATP 2+ More importantly, the estrogen-treated cells were protected in L-type Cachannel activity upon β -adrenoceptor 1 Kathie A WONG et al: β-Adrenoceptor and its Signaling Pathways in Cardioprotection by Female Sex Hormone 575 1 against hypoxia-reoxygenation injury and the effect was group also showed that 17β-estradiol or diarylpropionitrile given during resuscitation up-regulated the expression of blocked by blockade of the sarcolemmal Kchannel with ATP mitochondrial respiratory complex IV (MRC-IV), but in- HMR1098. The observations suggest that estrogen may enhance the expression of the sarcolemmal Kchannel, hibited the cytochrome C released from mitochondria 24 h ATP [34]known to protect the heart against ischemic insults. . This was accompanied by improved after resuscitation In a series of recent studies by Chaudry and co-workers, contractile recovery. The effects were abolished by blockade [31] [32] male ratsor OVX female ratswere subjected to of the MRC-IV inhibitor, sodium cyanite. Therefore acti- trauma-haemorrhage shock. Administration of 17β-estra- vation of the ER up-regulated MRC-IV, which inhibited diol during resuscitation improved the contractile recovery the release of cytochrome C from mitochondria, thus re- determined 24 h after the shock and the effect of estrogen ducing apoptosis and improving contractile recovery. This was abolished by blockade of the ER with a selective is similar to the suppression of CaMKII, known to induce [8]antagonist, ICI182,780, in OVX female rats, thus indicat- apoptosis via the cytochrome C release. [32]ing a receptor-mediated action. Further studies showed Acute administration of 17β-estradiol has also been re- that activation of the ER with diarylpropionitrile, a selec- ported to produce infarct sparing and anti-arrhythmic ef- [35]tive ER-β agonist, produced the same effects as 17β- fect induced by ischemia and reperfusion in dogs. The estradiol, indicating that the ER-β is the specific ER sub- cardioprotective effects of estrogen appears to be mediated [33]2++ type mediating the action of estrogen. The study also by nitric oxide and opening of the Ca-activated Kchan- [35]showed that estrogen conferred cardioprotection against nel in dogs. In addition, acute administration of a trauma-haemorrhage via the ER which up-regulated the supraphysiological concentration of estrogen has also been 2+ 2+ peroxisome proliferator-activated receptor coactivator-1 shown to inhibit the influx of Cavia the L-type Cachan- [36](PGC-1) through the mitochondrial transcription factor A nel in isolated ventricular myocytes. The effect may be (Tfam)-dependent pathway. A parallel study by the same mediated via a non-genomic pathway. Fig. 1. A summary of the interaction between estrogen and β -adrenoceptor and its downstream signaling pathways based on the available 2+evidence. Estrogen down-regulates the β-adrenoceptor as well as suppresses protein kinase A (PKA) and Ca/calmodulin kinase II (CaMKII). 12+ 2+ +2+ They in turn affect the Cahomeostasis via its actions on its effectors, the L-type Cachannel, ranodine receptor (RyR) and Na-Caexchanger (NCX), and enhance apoptosis, respectively. The effects are estrogen receptor-mediated. The question mark indicates preliminary result. PLB, phospholamban. Q. Subtype-specific alpha1- and beta-adrenoceptor signaling in 10 Conclusion the heart. Trends Pharmacol Sci 2006; 27: 330-337. Accumulating evidence has highlighted the many impor- Bers DM. Cardiac excitation-contraction coupling. 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