Cardioprotection by the female sex hormone -interaction with the β1-adrenoceptor and its signaling pathways

( views:129, downloads:0 )
Kathie A WONG()
Yan MA()
Wing-Tim CHENG()
Tak-Ming WONG(Tak-Ming WONG,Corresponding author.Tel:+86-852-28199194;Fax:+86-852-28559730;
Journal Title:
Volume 59, Issue 05, 2007
Key Word:
estrogen; β1-adrenoceptor; Ca2+/calmodulin kinase Ⅱ; protein kinase A; cardioprotection; apoptosis

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 β1-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G8 protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca2+/calmodulin kinase Ⅱδc isoform (CaMKII-δc), another downstream second messenger of the β1-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial β1-adrenoceptor and attenuate Ca2+ influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the β-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the β1-adrenoceptor 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.

  • [1]Mendelsohn ME,Karas RH.The protective effects of estrogen on the cardiovascular system.N Engl J Med 1999; 340:1801-1811.
  • [2]Dubey RK,Imthurn B,Barton M,Jackson EK.Vascular consequences of menopause and hormone therapy:Importance of timing of treatment and type of estrogen.Cardiovasc Res 2005;66:295-306.
  • [3]Patterson E,Ma LM,Szabo B,Robinson CP,Thadani U.Ovariectomy and estrogen-induced alterations in myocardial contractility in female rabbits:Role of the L-type calcium channel.J Pharmacol Exp Ther 1998; 284:586-591.
  • [4]Xiao RP,Zhu W,Zheng M,Cao C,Zhang Y,Lakatta EG,Han Q.Subtype-specific alphal-and beta-adrenoceptor signaling in the heart.Trends Pharmacol Sci 2006; 27:330-337.
  • [5]Bers DM.Cardiac excitation-contraction coupling.Nature 2002;415:198-205.
  • [6]Zhang R,Khoo MS,Wu Y,Yang Y,Grueter CE,Ni G,Price EE Jr,Thiel W,Guatimosim S,Song LS,Madu EC,Shah AN,Vishnivetskaya TA,Atkinson JB,Gurevich VV,Salama G,Lederer WJ,Colbran RJ,Anderson ME.Calmodulin kinase Ⅱ inhibition protects against structural heart disease.Nat Med 2005; 11:409-417.
  • [7]Wang W,Zhu W,Wang S,Yang D,Crow MT,Xiao RP,Cheng H.Sustained betal-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway.Circ Res 2004; 95:798-806.
  • [8]Zhu WZ,Woo AYH,Yang DM,Cheng HP,Crow MT,Xiao RP.Activation of CaMKⅡ delta C is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis.J Biol Chem 2007; 282:10833-10839.
  • [9]Schomig A,Richardt G.The role of catecholamines in ischemia.J Cardiovasc Pharmacol 1990; 16:S105-S112.
  • [10]Waldenstrom AP,Hjalmarson AC,Thornell L.A possible role of noradrenaline in the development of myocardial infarction:an experimental study in the isolated rat heart.Am Heart J 1978;95:43-51.
  • [11]Kam KWL,Qi JS,Chen M,Wong TM.Estrogen reduces cardiac injury and expression of β1 adrenoceptor upon ischemic insult in the rat heart.J Pharmacol Exp Ther 2004; 309:8-15.
  • [12]Ciric O,Susic D.Effect of isoproterenol on blood-pressure and heart-rate in different phases of the estrous-cycle.Endokrinologie 1980; 76:274-278.
  • [13]Kam KWL,Kravtsov GM,Liu J,Wong TM.Increased PKA activity and its influence on isoprenaline-stimulated L-type Ca2+channels in the heart from ovariectomized rats.Br J Pharmacol 2005; 144:972-981.
  • [14]Nikolic I,Liu DX,Bell JA,Collins J,Steenbergen C,Murphy E.Treatment with an estrogen receptor-beta-selective agonist is cardioprotective.J Mol Cell Cardiol 2007; 42:769-780.
  • [15]Thawornkaiwong A,Preawnim S,Wattanapermpool J.Upregulation of β1-adrenergic receptors in ovariectomized rat hearts.Life Sci 2003; 72:1813-1824.
  • [16]Li HY,Bian JS,Kwan YW,Wong TM.Enhanced responses to 17β-estradiol in rat hearts treated with isoproterenol:Involvement of a cyclic AMP-dependent pathway.J Pharmacol Exp Ther 2000; 293:592-598.
  • [17]Meyer R,Linz KW,Surges R,Meinardus S,Vees J,Hoffmann A,Windholz O,Grohé C.Rapid modulation of L-type calcium current by acutely applied oestrogens in isolated cardiac myocytes from human,guinea-pig and rat.Exp Physiol 1998; 83:305-321.
  • [18]Kravtsov GM,Kam KW,Liu J,Wu S,Wong TM.Altered Ca2+ handling by ryanodine receptor and Na+-Ca2+ exchange in the heart from ovariectomized rats:role of protein kinase A.Am J Physiol Cell Physiol 2007; 292:C1625-C1635.
  • [19]Ren J,Hintz KK,Roughead ZK,Duan J,Colligan PB,Ren BH,Lee KJ,Zeng H.Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation.Am J Physiol Heart Circul Physiol 2003; 284:H1800-H1807.
  • [20]Bupha-Intr T,Wattanapermpool J.Regulatory role of ovarian sex hormones in calcium uptake activity of cardiac sarcoplasmic reticulum.Am J Physiol Heart Circ Physiol 2006; 291:H1101-H1108.
  • [21]Clusin WT.Caffeine induces a transient inward current in cultured cardiac-cells.Nature 1983; 301:248-250.
  • [22]Clusin WT,Fischmeister R,Dehaan RL.Caffeine-induced current in embryonic heart cells:time course and voltage dependence.Am J Physiol 1983; 245:H528-H532.
  • [23]Curl CL,Wendt IR,Canny BJ,Kotsanas G.Effects of ovariectomy and 17 beta-oestradiol replacement on[Ca2+]i in female rat cardiac myocytes.Clin Exp Pharmacol Physiol 2003; 30:489-494.
  • [24]Krause EG,Curtis KS,Markle JP,Contreras RJ.Oestrogen affects the cardiovascular and central responses to isoproterenol of female rats.J Physiol 2007; 582 (Ptl):435-447.
  • [25]Collins P,Rosano GM,Jiang C,Lindsay D,Sarrel PM,PooleWilson PA.Cardiovascular protection by oestrogen-a calcium antagonist effect? Lancet 1993; 341:1264-1265.
  • [26]Jiang C,Poolewilson PA,Sarrel PM,Mochizuki S,Collins P,Macleod KT.Effect of 17-beta-estradiol on contraction,Ca2+current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes.Br J Pharmacol 1992; 106:739-745.
  • [27]Johnson BD,Zheng W,Korach KS,Scheuer T,Catterall WA,Rubanyi GM.Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice.J Gen Physiol 1997; 110:135-140.
  • [28]Wattanapermpool J.Increase in calcium responsiveness of cardiac myofilament activation in ovariectomized rats.Life Sci 1998;63:955-964.
  • [29]Wattanapermpool J,Riabroy T,Preawnim S.Estrogen supplement prevents the calcium hypersensitivity of cardiac myofilaments in ovariectomized rats.Life Sci 2000; 66:533-543.
  • [30]Ranki HJ,Budas GR,Crawford RM,Davies AM,Jovanovic A.17 beta-estradiol regulates expression of KATP channels in heartderived H9c2 cells.J Am Coll Cardiol 2002; 40:367-374.
  • [31]Mizushima Y,Wang P,Jarrar D,Cioffi WG,Bland KI,Chaudry IH.Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals.Ann Surg 2000; 232:673-679.
  • [32]Jarrar D,Wang P,Kn(o)ferl MW,Kuebler JF,Cioffi WG,Bland KI,Chaudry IH.Insight into the mechanism by which estradiol improves organ functions after trauma-hemorrhage.Surgery 2000;128:246-252.
  • [33]Hsieh YC,Yu HP,Suzuki T,Choudhry MA,Schwacha MG,Bland KI,Chaudry IH.Upregulation of mitochondrial respiratory complex Ⅳ by estrogen receptor-beta is critical for inhibiting mitochondrial apoptotic signaling and restoring cardiac functions following trauma-hemorrhage.J Mol Cell Cardiol 2006; 41:511-521.
  • [34]Hsieh YC,Choudhry MA,Yu HP,Shimizu T,Yang S,Suzuki T,Chen J,Bland KI,Chaudry IH.Inhibition of cardiac PGC-1α expression abolishes ERβ agonist-mediated cardioprotection following trauma-hemorrhage.FASEB J 2006; 20:1109-1117.
  • [35]Node K,Kitakaze M,Kosaka H,Minamino T,Funaya H,Hori M.Amelioration of ischemia-and reperfusion-induced myocardial injury by 17 beta-estradiol-Role of nitric oxide and calcium-activated potassium channels.Circulation 1997; 96:1953-1963.
  • [36]Ullrich ND,Koschak A,Macleod KT.Oestrogen directly inhibits the cardiovascular L-type Ca2+ channel Cavl.2.Biochem Biophys Res Commun 2007; 361:522-527.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615