Sex differences in expression of calcium-handling proteins and beta-adrenergic receptors in rat heart ventricle

Chu, Sang Hui; Sutherland, Karen; Beck, Jenny; Kowalski, Jill; Goldspink, Paul H.; Schwertz, Dorie W.

doi:10.1016/j.lfs.2004.12.013

Cited by 89 publications

(76 citation statements)

References 56 publications

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“…SERCA2a and PLB expression was similar in males and females; however, the increase in pS 16 -PLB in the females suggests less inhibition of SERCA2a activity in the females than males perhaps permitting greater calcium reentry into the SER. Our studies extend the results previously shown in rats where changes in NCX1, L-type calcium channel, and ryanodine receptor 2 expression in females relative to males (8) were correlated with differences in in vitro force development and relaxation. The conclusion is that sex influences the relative importance of proteins in maintaining calcium homeostasis.…”

Section: Discussionsupporting

confidence: 90%

“…Female rodents demonstrate smaller calcium transients and have reduced cardiac reserve, smaller changes in shortening, and less SER calcium loading compared with males after a catecholamine challenge (6,10,28,38). Baseline expression of calcium homeostasis proteins differs in male and female rats, and these differences were translated into differences in in vitro force development and relaxation (8). Ovariectomized (OVX) rats are hypersensitive to changes in calcium that is relieved by estradiol (35), and isolated cardiomyocytes from OVX hearts showed slow relaxation and contraction kinetics (5).…”

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confidence: 99%

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

Sebag

Gillis

Calderone

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

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

Sebag

Gillis

Calderone

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…A greater abundance of L-type Ca 2ϩ channel protein and dihydropyridine binding sites in concert with larger Ca 2ϩ current density (I ca ) have been reported in female myocytes (6,35). Expression of several calcium-handling proteins appears to be selectively regulated by estrogen, but the contribution to basal and pathologic contractile function is unclear (7). However, deletion of the estrogen receptor (ER), mainly the ␤-receptor isomer, induces alterations in the ECG parameters post-MI.…”

Section: Discussionmentioning

confidence: 99%

Sex-related changes in cardiac function following myocardial infarction in mice

Shioura¹,

Geenen²,

Goldspink³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Shioura KM, Geenen DL, Goldspink PH. Sex-related changes in cardiac function following myocardial infarction in mice. Am J Physiol Regul Integr Comp Physiol 295: R528 -R534, 2008. First published June 11, 2008 doi:10.1152/ajpregu.90342.2008.-Recent awareness of cardiovascular diseases as a number one killer of the middle-aged women has prompted interest in sex differences leading to heart failure (HF). Therefore, we evaluated cardiac function in female and male mice following myocardial infarction (MI) using the Millar pressure-volume (P-V) conductance system in vivo, at time points corresponding to early (2 wk), late compensatory hypertrophy (4 wk), and decompensation (10 wk) to HF. A significant deterioration of the load dependent and independent hemodynamic measurements occurred in both female and male mice during the early phase of hypertrophy. Later, compensatory hypertrophy was marked by a normalization of volumes to control levels in females compared with males. The most notable differences between sexes occurred in the measurements of cardiac contractility during the decompensation to HF. In females, there was a significant improvement in contractility compared with males, which was apparent in the load-independent measurements of preload recruitable stroke work (10 wk post-MI, female ϭ 48.7 Ϯ 8.0 vs. male ϭ 25.2 Ϯ 1.8 mmHg, P Ͻ 0.05) and maximum dP/dt vs. maximum end-diastolic volume (10 wk post-MI, femaleϭ359 Ϯ 58 vs. maleϭ149 Ϯ 28 mmHg ⅐ s Ϫ1 ⅐ l Ϫ1 , P Ͻ 0.05). Despite these differences, there were no differences in the heart weight to body weight ratio and infarct size between the sexes. These data demonstrate that compensatory hypertrophy is associated with an improvement in contractility and a delayed decompensation to HF in females. However, compensatory hypertrophy in males appears to be undermined by a steady decline in contractility associated with decompensation to HF. contractility; pressure-volume loops DAMAGE TO THE MYOCARDIUM FOLLOWING myocardial infarction (MI) is associated with compensatory responses such as left ventricular (LV) hypertrophy and activation of the sympathetic nervous system to maintain cardiac output. Eventually, these changes are inadequate and contractile dysfunction along with subsequent chamber dilation underlie the transition to heart failure (HF) (11, 32).There are known sex-related responses to ischemia following myocardial infarction (MI) ranging from symptoms, diagnoses, preventions, courses of disease and outcomes of existing therapies. Women have more diverse symptoms than men, which are the major causes for delayed diagnoses and treatments (18,29,37). Also, women have poorer outcomes for a number of clinical complications such as a non-Q wave MI and invasive percutaneous transluminal coronary angioplasty (16,25). Despite these sex differences in incidence, manifestation and outcome, clinical data on cardiac function changes following MI are obscured by numerous baseline differences such as age, risk factors, symptoms, and the presence of coexisting disease...

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“…96 Taken together, these data indicate a fundamental difference in the ability to contend with increased adrenergic drive between males and females despite a lack of evidence showing sex-dependent differences in adrenergic receptors. 97 In support of this sex effect, there are documented sex differences in Ca 2ϩ handling proteins related to adrenergic stimulation. 97 Although ovariectomized rats do not show a decrease in phospholamban mRNA levels, estrogen replacement elicits a significant increase in expression compared with ovariectomized and sham-operated animals.…”

Section: Transgenic Models Targeting Signaling Pathwaysmentioning

confidence: 95%

“…97 In support of this sex effect, there are documented sex differences in Ca 2ϩ handling proteins related to adrenergic stimulation. 97 Although ovariectomized rats do not show a decrease in phospholamban mRNA levels, estrogen replacement elicits a significant increase in expression compared with ovariectomized and sham-operated animals. 98 Similarly, the increase in Ca 2ϩ fluxes across the ryandine receptor and Na ϩ -Ca 2ϩ exchange in ovariectomized rats is reversed by estrogen treatment.…”

Section: Transgenic Models Targeting Signaling Pathwaysmentioning

confidence: 95%