Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice

Abstract

Sebag IA, Gillis MA, Calderone A, Kasneci A, Meilleur M, Haddad R, Noiles W, Patel B, Chalifour LE. Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice. Am J Physiol Heart Circ Physiol 301: H1706 -H1715, 2011. First published July 29, 2011; doi:10.1152/ajpheart.00088.2011.-Calcium flux into and out of the sarco(endo)plasmic reticulum is vitally important to cardiac function because the cycle of calcium entry and exit controls contraction and relaxation. Putative estrogen and androgen consensus binding sites near to a CpG island are present in the cardiac calsequestrin 2 (CSQ2) promoter. Cardiomyocytes express sex hormone receptors and respond to sex hormones. We hypothesized that sex hormones control CSQ2 expression in cardiomyocytes and so affect cardiac structure/function. Echocardiographic analysis of male and female C57bl6n mice identified thinner walled and lighter hearts in females and significant concentric remodeling after long-term gonadectomy. CSQ2 and sodium-calcium exchanger-1 (NCX1) expression was significantly increased in female compared with male hearts and decreased postovariectomy. NCX1, but not CSQ2, expression was increased postcastration. CSQ2 expression was reduced when H9c2 cells were cultured in hormone-deficient media; increased when estrogen receptor-␣ (ER␣), estrogen receptor-␤ (ER␤), or androgen agonists were added; and increased in hearts from ER␤-deficient mice. CSQ2 expression was reduced in mice fed a diet low in the methyl donor folic acid and in cells treated with 5-azadeoxycytidine suggesting an involvement of DNA methylation. DNA methylation in CpG in the CSQ2 CpG island was significantly different in males and females and was additionally changed postgonadectomy. Expression of DNA methyltransferases 1, 3a, and 3b was unchanged. These studies strongly link sex hormone-directed changes in CSQ2 expression to DNA methylation with changed expression correlated with altered left ventricular structure and function. protein expression; cardiac function MAINTENANCE OF THE EXPRESSION of calcium homeostasis is important for normal cardiac function (1, 13). Contraction is the consequence of the release of massive amounts of calcium into the cytosol from the sarco(endo)plasmic reticulum (SER) by ryanodine receptor 2. Relaxation is established by the combined action of the sodium-calcium exchanger-1 (NCX1) (30), which removes calcium to the cell exterior, and the sarco(endo)plasmic reticulum ATPase 2a (SERCA2a), which resequesters calcium back to the SER (19). Phospholamban (PLB) inhibits SERCA2a activity, but phosphorylation on either serine 16 (S 16 ) or threonine 17 (T 17 ) relieves this inhibition. Calsequestrin 2 (CSQ2) may be uniquely important for calcium signaling because it is the principal calcium storage protein in the SER and, as part of a protein complex with the ryanodine receptor 2, helps to control the amount of calcium released for contraction (7).The available evide...

Association of <b><i>AGTR1</i></b> Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

“…This may result from variable exposure to environmental factors such as smoking, alcohol consumption, high sodium diet, and physical activity between males and females [Christensen et al, 2009;Breitling et al, 2011;Philibert et al, 2012;Ronn et al, 2013]. In addition, sex hormones have been documented to regulate specific DNA methylation alterations [Sebag et al, 2011]. Therefore, the gender differences of AGTR1 methylation levels may reflect the differences of sex hormones and some non-heritable risk factors of EH between males and females.…”

Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training

“…SERCA2a resequesters calcium back to the SER allowing relaxation (15). Regulated expression of calcium homeostasis proteins, including CSQ2 and SERCA2a, is modified by sex and sex hormones (1,12,30,56), suggesting a possible interaction between female sex and DOX sensitivity.Dexrazoxane (DEX; ICRF-187, Zinecard; Pharmacia) [(ϩ)-1,2-bis (3,5-dioxopiperazinyl-1-yl) propane] (57) has a higher affinity for iron than DOX. Its use as a cardioprotectant is predicated on the finding that DEX reduces DOX-Fe 3ϩ complex formation, thereby lowering DOX-induced oxidative stress (28).…”

“…SERCA2a resequesters calcium back to the SER allowing relaxation (15). Regulated expression of calcium homeostasis proteins, including CSQ2 and SERCA2a, is modified by sex and sex hormones (1,12,30,56), suggesting a possible interaction between female sex and DOX sensitivity.…”

Androgen deprivation therapy and cardiovascular complications

“…Gonadectomy leads to concentric heart remodeling characterized by increased left ventricular posterior wall, reduced left ventricular internal diameter in diastole, and increased relative wall thickness (27). The absence of androgens after myocardial infarction can lead to increased apoptosis of cardiomyocytes, more extensive remodeling and impaired left ventricular function (28).…”

“…Androgens modulate cAMP/PKA and CaMKII pathways. Gonadectomy leads to reduction of phosphorylation of phospholamban at the CaMKII site and the proteinkinase A-site (27). Testosterone deprivation has no effect on myofi lament Ca 2+ sensitivity but decreases the maximal myofi lament responses to Ca…”