Open Access
Volume 7, Number 2, June 2017
Article Number 11
Number of page(s) 6
Published online 14 June 2017

© Author(s) 2017. This article is published with open access by China Medical University

Licence Creative Commons
Open Access This article is distributed under terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided original author(s) and source are credited.

1. Introduction

Cardiovascular disease is the leading cause of death worldwide. Millions of patients succumb to the consequences of myocardial ischemia, heart failure, and arrhythmias. Heart disease usually develops as a result of the deterioration of function of the myocardium, which leads to heart failure. The incidence of heart disease is low in premenopausal women but increases substantially after menopausal, suggesting that sex steroid hormones protect the female heart [1]. Cardiovascular cells express estrogen receptors (ERs) that are important targets for endogenous estrogen. Estrogen-ER complexes serve as transcription factors that promote gene expression which fortifies cardiac health [2]. Accumulating evidence from in vivo and in vitro studies suggests that 17 beta-estradiol (E2); the most abundant and active estrogen in premenopausal women; contribute to cardioprotection by preventing cardiomyocyte apoptosis and by alleviating left ventricular hypertrophy and cardiac fibrosis in women. Although estrogen replacement therapies on postmenopausal women and ovariectomized animal models are reported to suppress cardiac cell survival they promote other cardio vascular complications [3, 4].

thumbnail Fig. 1

Anti-apoptotic mechanism of phytoestrogen against extrinsic apoptosis: Similar to E2, phytoestrogens elevates the activity of PI3K-Akt to inhibit the JNK1/2 mediated activation and nuclear translocation of NFkB and thereby alleviates the LPS-induced cardiomyocyte apoptosis.

thumbnail Fig. 2

Anti-apoptotic mechanism of phytoestrogens against mitochondria associated apoptosis. Phytoestrogens potentially enhance PI3K-Akt activity and alleviates calcium accumulation in the cardiomyocytes by inhibiting the calcineurin mediated dephosphorylation of Bad to attenuate ISO induced apoptosis.

thumbnail Fig. 3

Phytoestrogens ameliorate IGF2R mediated cardiomyocyte apoptosis. Alike E2phytoestrogens may act against IGF2R-induced hypertrophy and cardiomyocyte death by inhibiting the Gαq mediated activation of cakineurin.

Therefore, further investigations are needed to fully understand the complex effects of estrogen and ERs on cardiomyocyte biology prior to its clinical application for cardiomyopathy treatment. This article will outline the basic molecular understanding of estrogen and ERs and review the current state of knowledge of estrogen signaling in cardiomyocyte protection. Further highlight the current knowledge on potential analogs such as the phytoestrogens that can be used to enhance cardiac health.

2. Structural characteristics of ERs and the events in E2/ER signaling

The most well-known physiological actions of E2 are mediated by two ER subtypes, ER-alpha (ERα) and ER-beta (ERβ), belonging to the member of the nuclear receptor superfamily and possess similar structural characteristics. The ERα and ERβ are transcribed from different genes and display distinct expression patterns as well as different ligand specificities [5]. These ERs constitutes five distinct domains that include A/B, C, D, E and F domains [6]. The A/B domain in ERα and ERβ share less than 20% amino acid homology and thereby contribute ER subtype-specificity on target genes. The activation function 1 element of the A/B domain provides the ability of ligand-independent ER activation [7].

The central C-domain is critical for specific DNA binding and dimerization of ERs and D-domain is important for ER nuclear translocation and is the hinge domain between the DNA-binding domain (DBD) and the E-domain which harbors a hormone-dependent activation function 2 (AF-2) element [8, 9]. The functions of the F-domain are not unclear.

Recently, the estrogen receptor GPR30 was identified as an orphan G-protein coupled receptor and estrogen is its endogenous ligand. As a transmembrane ER, GPR30 activation may mediate E2 rapid cell signaling [10]. The exact effects and molecular mechanism of GPR30 in cardiomyocytes has not been fully evaluated yet.

Estrogens bind to ERs to form the nuclear estrogen-ER complex which then binds to estrogen response element sequences (ERE) in the regulatory regions of the respective estrogen responsive genes, resulting in the appropriate expression. ERs modulate gene expressions by either binding to the ERE-mediated signaling or even by interacting directly or indirectly with transcription factors; this phenomenon is known as genomic ER signaling. Alternatively in non-genomic ER signaling, estrogen binds to ERs via cytoplasmic signal transduction proteins, such as mitogen activated protein kinase (MAPKs), Stats (signal transducers and activators of transcription), and Src family tyrosine kinases, or through membrane-associated estrogen-binding receptors, resulting in cellular responses [11]. ER bind to phosphoinositide-3 kinase (PI3K) to increase PI3K activity and thereby activates Akt to enhance pro-survival signaling in cardiomyocytes [12]. Growth factors such as insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) also interact with respective receptor tyrosine kinases and induce mitogen-activated protein kinase signaling, which in turn activates ER [13]. The third estrogen receptor, known as GPR30 (G-protein coupled estrogen receptor) was recently identified as the membrane-localized estrogen receptor and is located primarily on the plasma, endoplasmic reticulum and nuclear membrane [14].

3. Phytoestrogens: as a replacement to estrogen?

An increasing number of reports on hormone replacement therapy show that there is growing scientific interest focused on alternative therapies for postmenopausal women with a predisposition to CVD. Phytoestrogens are interesting candidates in this regard since they are structurally similar to estrogens [15]. They act as both estrogenic agonists and antagonists. Numerous herbs and medicinal plants are known to contain components similar t estrogen. Danshen is used widely in China for the treatment of cardiovascular disorders, including coronary heart disease. Danshen possesses lipid-soluble biologically active components with a structure similar to 17β-estrodiol (E2) [16]. Salvianolic acid B is an effecient phytoestrogen purified from danshen that show cardio protective effects by suppressing the apoptotic effect of treatment with high glucose combined with hypoxia in embryonic stem cell derived cardiomyocytes [17]. Resveratrol is a phytoestrogen naturally found in grapes and is a major constituent of wine thought to exert both cardioprotective and chemopreventive activities [18]. Recent studies show that this bioflavonoid binds to and activates gene transcription via ERα and ERβ. A recent report shows that Resveratrol enhanced FOXO3 phosphorylation via synergetic activation of SIRT1 and PI3K/Akt signaling to improve the effects of exercise in elderly rat hearts [19]. Epigal-locatechin-3-gallate (EGCG) is another phytoestrogen, abundant in green tea, which is known to inhibit cardiac myocyte apoptosis and oxidative stress in pressure overload induced cardiac hypertrophy [20]. Also, EGCG prevents cardiomyocyte apoptosis from oxidative stress in vitro [21]. Substantial evidence suggests that EGCG acts as an antioxidant by attenuating lipid peroxidation caused by various forms of ROS [22], thereby reducing the expression of the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine [23] as well as reducing the expression of cytokine-induced vascular adhesion molecule-1 [24]. EGCG also prevents the oxidized low-density lipoprotein-induced LOX-1-mediated biological events that are closely linked to endothelial dysfunction.

4. Phytoestrogen potentially modulate E2/ERs signaling to establish protection against LPS-induced myocardial cell death.

Lipopolysaccharides (LPSs), the outer-membrane component of Gram-negative bacteria, elevate inflammation and apoptosis by interacting with toll-like receptor-4 (TLR-4) resulting in sepsis-induced heart failure and [25, 26]. The LPS-induced myocardial apoptosis is mediated by JNK1/2, which promotes the activation of NFkB, leading to the increase of pro-apoptotic proteins such as TNFα (Tumor necrosis factor), active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9 and active caspase-3 [27]. The elevated PI3K-Akt activity mediated by E2 and ERα, contributing to the inhibition of nuclear translocation of NFkB and therefore diminishes the LPS-induced cardiomyocyte apoptosis (Fig. 1) [28]. This may suggest how menopausal women with sepsis have lower mortality and heart failure incidence.

Notoginsenoside R1 isolated from Panax notoginseng, is a major phytoestrogen effective against inflammation and apoptosis. Notoginsenoside R1 is known to regulate LPS induced NF-kB activation and related inflammation signaling involving TNF-a, IL-1b and IL-6. The mechanism by which Notoginsenoside R1 ameliorates LPS induced cardiac dysfunction involves activation of ERα and t PI3K/Akt survival signaling pathway [29]. Resveratrol is yet another phytoestrogen that suppresses proinflammatory cytokine production and prove to be effective against LPS endotoxin myocardial injury in mice [30, 31]. Apigenin, a flavone found in many fruits, vegetables and nuts are also known to reduce inflammation associated cardiac injury. Apigenin is known to down-regulate LPS induced inflammation associated TNF-α and IL-6 and IL-1β levels in heart and apoptosis associated cleaved caspase-3, cleaved caspase-9 and Bax levels in rat hearts [32].

5. Phytoestrogens modulate E2/ERs signaling and protects against apoptosis induced by hypertrophic agents

Cardiac hypertrophy is one of the most frequent causes of heart failure and it could results Cardiac insults like hypertension or by various hypertrophic agents [3336]. The early compensative hypertrophy often progress to become pathological, resulting in cardiomyocyte apoptosis and leading to eventual deterioration of cardiac function.

Calcium-sensitive phosphatease, calcineurin play a major role in cardiac hypertrophy. The calcineurin activity is increased by a variety of isoproterenol (Iso) [36]. Calcineurin activation promotes the NFAT3 nuclear translocation and activates MEF2 (myocyte-enhancing factor 2), resulting in the up-regulation of hypertrophic genes [37].

The results from various animal studies indicate that estrogen may defend against the development of cardiac hypertrophy.

We recently showed that E2 and ERβ alleviate isoproterenol-induced cellular calcium accumulation in cardiomyocytes by activating phospholamban and PI3K-Akt-MDM2 signaling cascades [38, 39] which increase the Q5 protein degradation of calcineurin. Therefore, E2/ ERβ inhibit isoproterenol-induced myocardial cell hypertrophy and apoptosis (Figure 2). On the other hand, ERa seems to have distinctive protective mechanism against Iso-induced hypertrophy and apoptosis in myocardial cells. Our lab has recently indentified that E2 facilitate the increase of interaction between ERa and Src results in the activation of IGFIR-PI3K-Akt and EGFR-MMP2/9-MEK1/2-ERK1/2 signaling pathways thereby reduces the calcineurin induced pro-apoptotic protein levels and protects cardiomyocytes from Iso-induced apoptosis (results from our unpublished data). E2 activates Src and heparin-bound epidermal growth factor (EGF) and thereby activates the EGF receptor with subsequent acute activation of PI3K and ERK activation [40].

Treatment with Genistein on H9c2 cardiomyoblasts suppresses the Iso induced apoptosis by reducing the mitochondrial pro-apoptotic proteins including Bad, caspase-8, caspase-9, and caspase-3 and by enhancing p-Akt, p-Bad, and p-Erk1/2 [41]. Phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension through Erβ [42]. Genistein has been proven to prevent phenylephrine induced cardiac muscle hypertrophy by inhibiting ERK1/2 and also potentially attenuate pressure overload-induced cardiac hypertrophy and fibrosis [43, 44].

6. Phytoestrogens mimic E2/ERs mediate cardio-protection against oxidative stress and ischemic-reperfusion injury

Ischemic heart disease (IHD) attributes to myocardial infarction or traumatic injury and it is one of the major cause of death and hospitalization in many countries [45]. The reduced blood supply induces a hypoxic situation of the heart muscle, which usually stimulates cytokines production, such as IL-6, leading to inflammation in myocardium and cardiomyocytes apoptosis [46, 47]. Ischemia-reperfusion injury is the damage caused by reestablishment of blood flow and re-oxygenation to the infracted tissue. Premenopausal women have lower incidence of IHD than men of same age probably due to the role of E2 and various epidemiological studies also indicate the same [48]. Estrogen replacement therapy reduces the infarct size and reduces of apoptosis in the peri-infarct zone of the left ventricle in coronary artery ligation animal model, suggesting that estrogen can effectively protect hearts against myocardial ischemia reperfusion injury [49].

Hypoxia-induced BNIP3 plays an important role in the development of hypoxia-induced cardiac hypertrophy and cardiomyocyte death [50]. We have recently found that ERα may bind to the regulatory region of BNIP3 gene, which is probably located on AP-1 or NFkB binding site within the promoter, leading to the suppression of BNIP3 transcriptional level. Meanwhile, the binding of ERα and BNIP3 proteins seems to facilitate proteasomes-mediated degradation of BNIP3. These two distinct ERα meditated effects contribute to the reduction in the BNIP3-induced cardiomyocyte apoptosis (results from our unpublished data). On the other hand, the elevated levels of oxidative stress and reactive oxygen species (ROS) during the reperfusion stage of ischemia-reperfusion injury also cause cardiomyocyte death [51, 52]. E2, either by activating ERα or ERβ, results in the activation of PI3K with subsequent inhibition of ischemia-reperfusion injury induced ROS and attenuation of apoptosis in the ischemic area [5356].

Dietary supplementation of phytoestrogens protect heart from ischemia, followed by normothermic reperfusion in rats by maintaining the ER mediated NO release, mitochondrial structure and function and by attenuating myocardial Ca2+accumulation [57]. In rats EGCG have been shown to protect myocardial reperfusion injury by specific inhibition of the IKK/NF-kB and AP-1 pathway [58]. Intravenous administration of genistein effectively attenuates cell death in the myocardial necrosis and MPO activity in the infracted tissue, and improves myocardial contractile function by limiting the inflammatory response after ischaemia-reperfusion injury in animal models [59, 60]. Experimental and clinical investigation show that they phytoestrogen danshen protects hearts against hypertrophy and ischemia-reperfusion injury [61].

7. E2/ERs and the analogous phytoestrogens mediate cardio-protection against IGF2R death signal

Insulin-like growth factors receptor II (IGF2R) or the cation-independent mannose-6-phosphate receptor, is a protein that in humans was initially thought to be responsible for quenching IGF2 ligand [62]. Activation of IGF2R in cardiomyocytes is induced by hypertension, AngII and Inomycin. Suppression of IGF2R leads to cardiomyocytes apoptosis and leads to the MMP2/9 activation and myocardial ECM remodeling [63-65]. Our recent investigations show that the activation of PI3K-Akt pathway by E2 markedly attenuated IGF2R-induced apoptosis and hypertrophy in cardiomyocytes. These data indicate that E2 has protective effects against IGF2R-induced hypertrophy and cardiomyocyte death (Fig. 3). More research is necessary to characterize whether this protection is ER-dependent and to reveal the precise mechanisms responsible for this cardioprotection.

Our previous findings show that Danshen acts through ER to activate Akt and attenuate activation of IGF-II receptor signaling and inhibit apoptosis [66].

8. Conclusions and future perspective

ERα, ERβ confer cardioprotective effects against various stresses by preventing myocardial cell apoptosis and cardiac function. Our laboratory is investigating the possible regulation of autophagy by estrogen and ER-mediated cardioprotection. This is critical to understand the complex nature of cellular mechanisms of estrogen and ERs in various heart diseases, such as ischemic injury, cardiac hypertrophy, cardiac remodeling, and heart failure. Further we evaluate various phytoestrogens in promoting cardiac cell survival and function which would enable in the process of establishing alternatives for estrogen replacement treatments.


  1. Pekka J, Erkki V, Jaakko T, Pekka P. Age, Cardiovascular risk factors, and coronary heart disease. Circulation. 1999, 99, 1165–1172. [CrossRef] [PubMed] (In the text)
  2. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, et al. American Heart Association. Hormone Replacement Therapy and Cardiovascular Disease. Circulation. 2001, 104 (4), 499–503. [CrossRef] [PubMed] (In the text)
  3. Patten Richard D, Richard K. Estrogen replacement and cardiomyocyte protection. Trends Cardiovasc Med. 2006, 16, 69–75. [CrossRef] [PubMed] (In the text)
  4. Rosano GM, Vitale C, Silvestri A, Fini M. Hormone replacement therapy and cardioprotection: the end of the tale?. Ann N Y Acad Sci. 2003, 997, 351–357. (In the text)
  5. Gustafsson JA.. Estrogen receptor β - a new dimension in estrogen mechanism of action. J Endocrinol. 1999, 163, 379–383. [CrossRef] [PubMed] (In the text)
  6. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol. 1998, 384–391. [CrossRef] [PubMed] (In the text)
  7. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007, 87, 905–931. [CrossRef] [PubMed] (In the text)
  8. Schwabe JW, Neuhaus D, Rhodes D. Solution structure of the DNA- binding domain of the oestrogen receptor. Nature. 1990, 29, 45861. (In the text)
  9. Chunyan Z, Karin D-W, Jan-A G. Estrogen receptor β: an overview and update. Nucl Recept Signal. 2008, 6, e003. [PubMed] (In the text)
  10. Eric P, Jeffery A, Harriet S, Tudor O, Larry S, Helen H. Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu. Rev. Physiol. 2008, 70, 165–190. (In the text)
  11. Kim JK, Levin ER. Estrogen signaling in the cardiovascular system. Nucl Recept Signal. 2006, 4e013. (In the text)
  12. Richard D, Isaac P, Mark J, Aronovitz Jason B, Flore C, et al. 17β-Estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of Phospho-inositide-3 kinase/Akt signaling. Circulation Research. 2004, 95, 692. [CrossRef] [PubMed] (In the text)
  13. Lannigan DA. Estrogen receptor phosphorylation. Steroid. 2003, 68 (1), 1–9. [CrossRef] (In the text)
  14. Eric P, Matthias B. Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER. Prostaglandins other Lipid Mediat. 2009, 89, 89–97. (In the text)
  15. Bhupathy P, Haines CD, Leinwand LA. Influence of sex hormones and phytoestrogens on heart disease in men and women. Womens Health. 2010, 6, 77–95. (In the text)
  16. Weng YS, Kuo WW, Lin YM, Kuo CH, Tzang BS, Tsai FJ, et al. Danshen mediates through estrogen receptors to activate Akt and inhibit apoptosis effect of Leu27IGF-II-induced IGF-II receptor signaling activation in cardiomyoblasts. Food Chem Toxicol. 2013, 56, 28–39. [CrossRef] [PubMed] (In the text)
  17. Huang CY, Chen SY, Fu RH, Huang YC, Chen SY, Shyu WC, et al. Differentiation of embryonic stem cells into cardiomyocytes used to investigate the cardioprotective effect of salvianolic acid B through BNIP3 involved pathway. Cell Transplant. 2015. (In the text)
  18. Henry LA, Witt DM. Resveratrol: phytoestrogen effects on reproductive physiology and behavior in female rats. Horm Behav. 2002 , 41, 220–228. (In the text)
  19. Lin CH, Lin CC, Ting WJ, Pai PY, Kuo CH, Ho TJ, et al. Resveratrol enhanced FOXO3 phosphorylation via synergetic activation of SIRT1 and PI3K/Akt signaling to improve the effects of exercise in elderly rat hearts. Age (Dordr) 2014, 36, 9705. (In the text)
  20. Sheng R, Gu ZL, Xie ML, Zhou WX, Guo CY. EGCG inhibits cardiomyocyte apoptosis in pressure overload-induced cardiac hypertrophy and protects cardiomyocytes from oxidative stress in rats. Acta Pharmacol Sin. 2007, 28: 191–201. [CrossRef] [PubMed] (In the text)
  21. Ou HC, Song TY, Yeh YC, Huang CY, Yang SF, Chiu TH, et al. EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling. J Appl Physiol. 2010, 108: 1745–1756. [CrossRef] [PubMed] (In the text)
  22. Guo Q, Zhao B, Li M, Shen S, Xin W. Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta. 1996 , 1304: 210–222. (In the text)
  23. Tang WJ, Hu CP, Chen MF, Deng PY, Li YJ. Epigallocatechin gal-late preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level. Can J Physiol Pharmacol. 2006, 84: 163–171. [CrossRef] [PubMed] (In the text)
  24. Ludwig A, Lorenz M, Grimbo N, Steinle F, Meiners S, Bartsch C, et al. The tea flavonoid epigallocatechin-3-gallate reduces cytokine- induced VCAM-1 expression and monocyte adhesion to endothelial cells. Biochem Biophys Res Commun. 2004, 316: 659–665. [PubMed] (In the text)
  25. Raetx CR, Whtifield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002, 71, 635–700. [CrossRef] [PubMed] (In the text)
  26. Tavener SA, Kubes P. Is there a role for cardiomyocyte toll-like receptor 4 in endotoxemia?. Trends Cardiovasc Med. 2005 , 15, 153–157. [CrossRef] [PubMed] (In the text)
  27. Liu CJ, Lo JF, Kuo CH, Chu CH, Chen LM, Tsai FJ, et al. Akt Mediates 17beta-estradiol and/or estrogen receptor alpha inhibition of LPS-induced tumor necrosis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. J Cell Mol Med. 2009, 13 (9b), 3655–3667. [CrossRef] [PubMed] (In the text)
  28. Theo P, Manfred N, Tertia J, Virginija J, Ludwig N. Estrogen effects in the myocardium: inhibition of NF-kB DNA binding by estrogen receptor-α and -β. Biochem Biophys Res Commun. 2001, 286 (5), 1153–1157. [PubMed] (In the text)
  29. Sun B, Xiao J, Sun XB, Wu Y. Notoginsenoside R1 attenuates cardiac dysfunction in endotoxemic mice: an insight into oestrogen receptor activation and PI3K/Akt signalling. Br J Pharmacol. 2013, 168 (7), 1758–1770. (In the text)
  30. Hao E, Lang F, Chen Y, Zhang H, Cong X, Shen X, et al. Resveratrol Alleviates Endotoxin-Induced Myocardial Toxicity via the Nrf2 Transcription Factor. PLoS One. 2013, 8 (7), e69452. (In the text)
  31. Zhang T, Yan T, Du J, Wang S, Yang H.. Apigenin attenuates heart injury in lipopolysaccharide-induced endotoxemic model by suppressing sphingosine kinase 1/sphingosine 1-phosphate signaling pathway. Chem Biol Interact. 2014, S0009-2797 (14), 00406–2. (In the text)
  32. Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, et al. Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats. Hypertension. 2012; 60 (2), 425–430. (In the text)
  33. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006, 7 (8), 589–600. [CrossRef] [PubMed] (In the text)
  34. Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffith R, Kumar AP, et al. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci. 2006, 3 (47), 17985–17990. [CrossRef]
  35. Barry SP, Davidson SM, Townsend PA. Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol. 2008, 40(10), 2023–2039. [CrossRef] [PubMed]
  36. Freund C, Schmidt-Ullrich R, Baurand A, Dunger S, Scheider W, Loser P, et al. Requirement of nuclear factor-kappaB in angiotensin II-and isoproterenol-induced cardiac hypertrophy in vivo. Circulation. 2005, 111 (18, 2319–2325. [CrossRef] [PubMed] (In the text)
  37. Beate F, Suzanne L, Albert S, Stephan L, Burkert P, Frank S, et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci. 2002, 99 (17), 11363–11368. [CrossRef] (In the text)
  38. Donaldson C, Eder S, Barker C, Aronovitz MJ, Weiss AD, Hall-Porter M, et al. Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circ Res. 2009 , 104 (2), 265–275. (In the text)
  39. Beate F, Suzanne L, Albert S, Stephan L, Burkert P, Frank S, et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci. 2002, 99 (17), 11363–11368. [CrossRef] (In the text)
  40. Filardo EJ, Quinn JA, Bland KI, FrackeltonJr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol. 2000, 14 (10), 1649–1660. (In the text)
  41. Hu WS, Lin YM, Ho TJ, Chen RJ, Li YH, Tsai FJ, et al. Genistein suppresses the isoproterenol-treated H9c2 cardiomyoblast cell apoptosis associated with P-38, Erk1/2, JNK, and NFkB signaling protein activation. Am J Chin Med. 2013, 41 (5), 1125–1136. [CrossRef] [PubMed] (In the text)
  42. Thorburn J, Thorburn A. The tyrosine kinase inhibitor, genistein, prevents alpha-adrenergic-induced cardiac muscle cell hypertrophy by inhibiting activation of the Ras-MAP kinase signaling pathway. Biochem Biophys Res Commun. 1994, 202 (3), 1586–1591. [PubMed] (In the text)
  43. Qin W, Du N, Zhang L, Wu X, Hu Y, Li X, et al. Genistein alleviates pressure overload-induced cardiac dysfunction and interstitial fibrosis in mice. Br J Pharmacol. 2014, [Epub ahead of print]. (In the text)
  44. Maulik SK, Prabhakar P, Dinda AK, Seth S. Genistein prevents isoproterenol-induced cardiac hypertrophy in rats. Can J Physiol Pharmacol 2012, 90 (8), 1117–1125. [CrossRef] [PubMed] (In the text)
  45. World Health Organization Department of Health Statistics and Informatics in the Information, Evidence and Research Cluster.(2004). The global burden of disease 2004 update. Geneva: WHO. (In the text)
  46. Antti S, Kari P, Markku K, Kenth H, Martti P, Liisa P. Apoptosis in human acute myocardial infarction. Circulation. 1997, 95, 320–323. [CrossRef] [PubMed] (In the text)
  47. Yang S, Zheng R, Hu S, Ma Y, Choudhry MA, Messina JL, et al. Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function. Am J Physiol Heart Circ Physiol. 2004, 287 (5), 2183–2191. (In the text)
  48. Hayward CS, Kelly RP, Collins P. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardio-vasc Res. 2000, 46 (1), 28–49. [CrossRef] (In the text)
  49. Yi Xu, Ivan A, Arenas Stephen A, Wayne P, Han Xu, et al. Estrogen improves cardiac recovery after ischemia/reperfusion by decreasing tumor necrosis factor α. Cardiovasc Res. 2006, 69, 836–844. (In the text)
  50. Weng YJ, Kuo WW, Kuo CH, Tung CH, Tung KC, Tsai CH, et al. BNIP3 induces IL6 and calcineurin/NFAT3 hypertrophic-related pathways in H9c2 cardiomyoblast cells. Mol Cell Biochem. 2010, 345, 241–247. (In the text)
  51. Vanden Hoek TL, Li C, Shao Z, Schumacker PT, Becker LB. Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion. J Mol Cell Cardiol. 1997, 29 (9), 2571–2583. [CrossRef] [PubMed] (In the text)
  52. Robin E, Guzy RD, Loor G, Iwase H, Waypa GB, Marks JD, et al. Oxidant stress during simulated ischemia primes cardiomyocytes for cell death during reperfusion. J Biol Chem. 2007, 282 (26), 1913343. (In the text)
  53. Liu H, Pedram A, Kim JK. Oestrogen prevents cardiomyocyte apoptosis by suppressing p38α-mediated activation of p53 and by down-regulating p53 inhibition on p38β. Cardiovas Res. 2011, 89 (1), 11928. (In the text)
  54. Lin J, Steenbergen C, Murphy E, Sun J. Estrogen receptor-β activation results in S-nitrosylation of proteins involved in cardioprotection. Circulation 2009, 120 (3), 245–254. [CrossRef] [PubMed]
  55. Urata Y, Ihara Y, Murata H, Goto S, Koji T, Yudoi J, et al. 17Beta-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells. J Biol Chem. 2006, 281 (19), 13092–02. [PubMed]
  56. Weil BR, Manukan MC, Hermann JL, Wang Y, Abaranrll AM, Poynter JA, et al. Signaling via GPR30 protects the myocardium from ischemia/reperfusion injury. Surgery. 2010, 148 (2), 436–443. (In the text)
  57. Zhai P, Eurell TE, Cotthaus RP, Jeffery EH, Bahr JM, Gross DR. Effects of dietary phytoestrogen on global myocardial ischemia-reperfusion injury in isolated female rat hearts. Am J Physiol Heart Circ Physiol. 2001, 281 (3), H1223–H1232. (In the text)
  58. Aneja R, Hake PW, Burroughs TJ, Denenberg AG, Wong HR, Zingarelli B. Epigallocatechin, a green tea polyphenol, attenuates myocardial ischemia reperfusion injury in rats. Mol Med. 2004, 10 (1-6), 55–62. [CrossRef] [PubMed] (In the text)
  59. Deodato B, Altavilla D, Squadrito G, Campo GM, Arlotta M, Minutoli L, et al. Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. Br J Pharmacol. 1999, 128 (8), 1683–1690. (In the text)
  60. Ji ES, Yue H, Wu YM, He RR. Effects of phytoestrogen genistein on myocardial ischemia/reperfusion injury and apoptosis in rabbits. Acta Pharmacol Sin. 2004, 25 (3), 306–312. [PubMed] (In the text)
  61. Takahashi K, Ouyang X, Komatsu K, Nakamura N, Hattori M, Baba A, et al. Sodium tanshinone IIA sulfonate derived from Danshen (Salvia miltiorrhiza) attenuates hypertrophy induced by angiotensin II in cultured neonatal rat cardiac cells. Biochem Pharmacol. 2002, 64 (4), 745–749. [CrossRef] [PubMed] (In the text)
  62. Pradipta G, Nancy D, Stuart K. Mannose-6-phosphate receptors: new twist in the tale. Nat Rev Mol Cell Biol. 2003, 4 (3), 202–212. [CrossRef] [PubMed] (In the text)
  63. Chang MH, Kuo WW, Chen RJ, Lu MC, Tsai FJ, Kuo WH, et al. IGF- II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells. J Mol Endocrinol. 2008, 41 (2), 65–74. [CrossRef] [PubMed] (In the text)
  64. Chu CH, Tzang BS, Chen LM, Kuo CH, Cheng YC, Chen YL, et al. IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via Galphaq interaction and protein kinase C-alpha/CaMKII activation in H9c2 cardiomyoblast cells. J Endocrinol. 2008, 197 (2), 381–390. [CrossRef] [PubMed]
  65. Chen RJ, Wu HC, Chang MH, Lai CH, Tien YC, Hwang JM, et al. Leu27IGF2 plays an opposite role to IGF1 to induce H9c2 cardio-myoblast cell apoptosis via Galphaq signaling. J Mol Endocrinol. 2009, 43 (6), 221–230. [CrossRef] [PubMed] (In the text)
  66. Weng YS, Kuo WW, Lin YM, Kuo CH, Tzang BS, Tsai FJ, et al. Danshen mediates through estrogen receptors to activate Akt and inhibit apoptosis effect of Leu27IGF-II-induced IGF-II receptor signaling activation in cardiomyoblasts. Food Chem Toxicol. 2013, 56, 28–39. [CrossRef] [PubMed] (In the text)

All Figures

thumbnail Fig. 1

Anti-apoptotic mechanism of phytoestrogen against extrinsic apoptosis: Similar to E2, phytoestrogens elevates the activity of PI3K-Akt to inhibit the JNK1/2 mediated activation and nuclear translocation of NFkB and thereby alleviates the LPS-induced cardiomyocyte apoptosis.

In the text
thumbnail Fig. 2

Anti-apoptotic mechanism of phytoestrogens against mitochondria associated apoptosis. Phytoestrogens potentially enhance PI3K-Akt activity and alleviates calcium accumulation in the cardiomyocytes by inhibiting the calcineurin mediated dephosphorylation of Bad to attenuate ISO induced apoptosis.

In the text
thumbnail Fig. 3

Phytoestrogens ameliorate IGF2R mediated cardiomyocyte apoptosis. Alike E2phytoestrogens may act against IGF2R-induced hypertrophy and cardiomyocyte death by inhibiting the Gαq mediated activation of cakineurin.

In the text

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