We studied the in vivo effects of estradiol on size and biochemical parameters of cardiomyocytes in pathophysiological conditions such as obesity and insulin resistance. Male Wistar rats were normally fed (controls, n = 7) or fed with high-fat diet (obese, n = 14). Half of the obese rats (obese + estradiol, n = 7) were treated with a single dose of estradiol (40 μg/kg, intraperitoneally) and 24 hours after treatment all the rats were killed. Estradiol in vivo in obese rats resulted in a significant increase in protein kinase B (Akt) activation (P < .05) and decrease in heart mass (P < .05), ratio of the heart mass/body mass (P < .05), transverse diameters of cardiomyocytes (P < .001), concentration of serum high-sensitivity C-reactive protein (P < .001), and total cholesterol (P < .01) compared with obese nontreated rats. Our results suggest that estradiol in obese/IR rats affects the size of cardiomyocytes and its actions lead in vivo to a reduction in obesity-induced cardiac hypertrophy, via Akt.
LehrkeMLazarMA. Inflamed about obesity. Nat Med. 2004;10(2):126–127.
3.
IacobellisGRibaudoMCLetoG. Influence of excess fat on cardiac morphology and function: study in uncomplicated obesity. Obes Res. 2002;10(8):767–773.
4.
IacobellisGRibaudoMCZappaterrenoAIannucciCVDi MarioULeonettiF. Adapted changes in left ventricular structure and function in severe uncomplicated obesity. Obes Res. 2004;12(10):1616–1621.
5.
OuwensDMBoerCFodorM. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia. 2005;48(6):1229–1237.
6.
LeopoldoASSugizakiMMLima-LeopoldoAP. Cardiac remodeling in a rat model of diet-induced obesity. Can J Cardiol. 2010;26(8):423–429.
7.
Barrett-ConnorEGiardinaEGGittAKGudatUSteinbergHOTschoepeD. Women and heart disease: the role of diabetes and hyperglycemia. Arch Intern Med. 2004;164(9):934–942.
8.
ShiHCleggDJ. Sex differences in the regulation of body weight. Physiol Behav. 2009;97(2):199–204.
9.
KnowltonAALeeAR. Estrogen and the cardiovascular system. Pharmacol Ther. 2012;135(1):54–70.
10.
MurphyE. Estrogen signaling and cardiovascular disease. Circ Res. 2011;109(6):687–696.
11.
SzalayLShimizuTSuzukiT. Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R812–R818.
12.
van EickelsMGroheCCleutjensJPJanssenBJWellensHJDoevendansPA. 17beta-estradiol attenuates the development of pressure-overload hypertrophy. Circulation. 2001;104(12):1419–1423.
13.
GardnerJDMurrayDBVoloshenyukTGBrowerGLBradleyJMJanickiJS. Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts. Am J Physiol Heart Circ Physiol. 2010;298(2):H497–H504.
14.
BarrosRPGustafssonJA. Estrogen receptors and the metabolic network. Cell Metab. 2011;14(3):289–299.
15.
HandgraafSRiantEFabreA. Prevention of obesity and insulin resistance by estrogens requires ERalpha activation function-2 (ERalphaAF-2), whereas ERalphaAF-1 is dispensable. Diabetes. 2014;62(12):4098–4108.
16.
PedramARazandiMAitkenheadMHughesCCLevinER. Integration of the non-genomic and genomic actions of estrogen. membrane-initiated signaling by steroid to transcription and cell biology. J Biol Chem. 2002;277(52):50768–50775.
17.
SudarEVelebitJGluvicZ. Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension. J Theor Biol. 2008;251(4):584–592.
18.
IsenovicERMengYJamaliNMilivojevicNSowersJR.AngIIattenuates IGF-1-stimulated Na+, K(+)-ATPase activity via PI3K/Akt pathway in vascular smooth muscle cells. Int J Mol Med. 2004;13(6):915–922.
19.
LingSDaiAWilliamsMR. The isoflavone metabolite cis-tetrahydrodaidzein inhibits ERK-1 activation and proliferation in human vascular smooth muscle cells. J Cardiovasc Pharmacol. 2004;43(5):622–628.
20.
Camper-KirbyDWelchSWalkerA. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res. 2001;88(10):1020–1027.
21.
KehatIMolkentinJD. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann N Y Acad Sci. 2010;1188:96–102.
22.
HaoLWangYDuanYBuS. Effects of treadmill exercise training on liver fat accumulation and estrogen receptor alpha expression in intact and ovariectomized rats with or without estrogen replacement treatment. Eur J Appl Physiol. 2010;109(5):879–886.
23.
KumagaiSHolmangABjorntorpP. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand. 1993;149(1):91–97.
24.
StubbinsRENajjarKHolcombVBHongJNunezNP. Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance. Diabetes Obes Metab. 2012;14(1):58–66.
25.
WagnerJDThomasMJWilliamsJKZhangLGreavesKACefaluWT. Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with estradiol alone or combined with nomegestrol acetate. J Clin Endocrinol Metab. 1998;83(3):896–901.
26.
ZhuLBrownWCCaiQ. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes. 2013;62(2):424–434.
27.
KoricanacGTepavcevicSZakulaZMilosavljevicTStojiljkovicMIsenovicER. Interference between insulin and estradiol signaling pathways in the regulation of cardiac eNOS and Na(+)/K(+)-ATPase. Eur J Pharmacol. 2011;655(1-3):23–30.
28.
LowryOHRosebroughNJFarrALRandallRJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–275.
29.
MatthewsDRHoskerJPRudenskiASNaylorBATreacherDFTurnerRC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–419.
30.
DuncombeWG. The colorimetric micro-determination of non-esterified fatty acids in plasma. Clin Chim Acta. 1964;9:122–125.
31.
StewartJC. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem. 1980;104(1):10–14.
32.
van SonJASmedtsFde WildePC. Histological study of the internal mammary artery with emphasis on its suitability as a coronary artery bypass graft. Ann Thorac Surg. 1993;55(1):106–113.
33.
LaemmliUK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227(5259):680–685.
34.
TowbinHStaehelinTGordonJ. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979;76(9):4350–4354.
35.
BurnetteWN. “Western blotting”: electrophoretic transfer of proteins from sodium dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem. 1981;112(2):195–203.
36.
DonaldsonCEderSBakerC. Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circ Res. 2009;104(2):265–275.
37.
MuraseTHattoriTOhtakeM. Effects of estrogen on cardiovascular injury in ovariectomized female DahlS.Z-Lepr(fa)/Lepr(fa) rats as a new animal model of metabolic syndrome. Hypertension. 2012;59(3):694–704.
38.
PattenRDPouratiIAronovitzMJ. 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res. 2004;95(7):692–699.
39.
HaleSLBirnbaumYKlonerRA. Estradiol, administered acutely, protects ischemic myocardium in both female and male rabbits. J Cardiovasc Pharmacol Ther. 1997;2(1):47–52.
40.
ThawornchaisitPde LoozeFReidCMSeubsmanSASleighA. Health-risk factors and the prevalence of hypertension: cross-sectional findings from a national cohort of 87,143 Thai open university students. Glob J Health Sci. 2013;5(4):126–141.
41.
SitesCKTischlerMDBlackmanJA. Effect of short-term hormone replacement therapy on left ventricular mass and contractile function. Fertil Steril. 1999;71(1):137–143.
42.
van EickelsMPattenRDAronovitzMJ. 17-beta-estradiol increases cardiac remodeling and mortality in mice with myocardial infarction. J Am Coll Cardiol. 2003;41(11):2084–2092.
43.
Gromadzka-OstrowskaJPrzepiorkaMRomanowiczK. Influence of dietary fatty acids composition, level of dietary fat and feeding period on some parameters of androgen metabolism in male rats. Reprod Biol. 2002;2(3):277–293.
44.
LiYYangJLiS. N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na+/K+-ATPase. J Biol Chem. 2011;286(37):32289–32299.
45.
ObradovicMBjelogrlicPRizzoM. Effects of obesity and estradiol on Na+/K+-ATPase and their relevance to cardiovascular diseases. J Endocrinol. 2013;218(3):R13–R23.
46.
BarrosRPMachadoUFWarnerMGustafssonJA. Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc Natl Acad Sci U S A. 2006;103(5):1605–1608.
ManriqueCLastraGHabibiJMugerfeldIGarroMSowersJR. Loss of estrogen receptor alpha signaling leads to insulin resistance and obesity in young and adult female mice. Cardiorenal Med. 2012;2(3):200–210.
49.
GorresBKBomhoffGLMorrisJKGeigerPC. In vivo stimulation of oestrogen receptor alpha increases insulin-stimulated skeletal muscle glucose uptake. J Physiol. 2011;589(pt 8):2041–2054.
50.
RiantEWagetACogoHArnalJFBurcelinRGourdyP. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 2009;150(5):2109–2117.
51.
BryzgalovaGLundholmLPortwoodN. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab. 2008;295(4):E904–E912.
52.
KoricanacGMilosavljevicTStojiljkovicM. Impact of estradiol on insulin signaling in the rat heart. Cell Biochem Funct. 2009;27(2):102–110.
53.
HotamisligilGS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140(6):900–917.
54.
JelenikTRodenM. How estrogens prevent from lipid-induced insulin resistance. Endocrinology. 2013;154(3):989–992.
55.
RodenM. Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes. Int J Obes (Lond). 2005;29suppl 2:S111–S115.
56.
SamuelVTPetersenKFShulmanGI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375(9733):2267–2277.
57.
ChristoffersenCBollanoELindegaardML. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology. 2003;144(8):3483–3490.
58.
TianYQLiS SSuXD. Effects of pioglitazone on high-fat-diet-induced ventricular remodeling and dysfunction in rats. J Cardiovasc Pharmacol Ther. 2012;17(2):223–228.
59.
ZibIJacobANLingvayI. Effect of pioglitazone therapy on myocardial and hepatic steatosis in insulin-treated patients with type 2 diabetes. J Investig Med. 2007;55(5):230–236.
60.
ZhouYTGrayburnPKarimA. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000;97(4):1784–1789.
61.
HewittKNPratisKJonesMESimpsonER. Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology. 2004;145(4):1842–1848.
62.
ResanovicIRizzoMZafirovicS. Anti-atherogenic effects of 17beta-estradiol. Horm Metab Res. 2013;45(10):701–708.
63.
MusatovSChenWPfaffDW. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(7):2501–2506.
64.
HsiehYCChoudhryMAYuH P. Inhibition of cardiac PGC-1alpha expression abolishes ERbeta agonist-mediated cardioprotection following trauma-hemorrhage. FASEB J. 2006;20(8):1109–1117.
65.
KoricanacGTepavcevicSRomicS. Estradiol enhances effects of fructose rich diet on cardiac fatty acid transporter CD36 and triglycerides accumulation. Eur J Pharmacol. 2012;694(1-3):127–134.
66.
TepavcevicSKoricanacGZakulaZMilosavljevicTStojiljkovicMIsenovicER. Interaction between insulin and estradiol in regulation of cardiac glucose and free fatty acid transporters. Horm Metab Res. 2011;43(8):524–530.
67.
JonesMEThorburnAWBrittKL. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A. 2000;97(23):12735–12740.
68.
BagatellCJKnoppRHRivierJEBremnerWJ. Physiological levels of estradiol stimulate plasma high density lipoprotein2 cholesterol levels in normal men. J Clin Endocrinol Metab. 1994;78(4):855–861.
69.
ZhengHLiYDaiWWeiCSunKTongY. Role of endogenous estrogen on the incidence of coronary heart disease in men. Angiology. 2012;63(8):591–596.
70.
LiuDBachmannKA. An investigation of the relationship between estrogen, estrogen metabolites and blood cholesterol levels in ovariectomized rats. J Pharmacol Exp Ther. 1998;286(1):561–568.
71.
El-NasrADiabFBahgatNAhmedMThabetSEl-DakkakS. Metabolic effects of estrogen and / or insulin in ovariectomized experimentally diabetic rats. J Am Sci. 2011;7(2):432–444.
72.
WangMTsaiBMReigerKMBrownJWMeldrumDR. 17-beta-Estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia. J Mol Cell Cardiol. 2006;40(2):205–212.
