Genetic background affects function and intracellular calcium regulation of mouse hearts

Shah, Adarsh; Siedlecka, Urszula; Gandhi, Ajay; Navaratnarajah, Manoraj; Al-Saud, Sara Abou; Yacoub, Magdi H.; Terracciano, Cesare M.

doi:10.1093/cvr/cvq111

Cited by 40 publications

(44 citation statements)

References 38 publications

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“…The C57bl/6 mice were equated to have an "athlete's heart" when compared with A/J mice, yet the C57bl/6 mice were not deliberately exercised. Similarly, when healthy and unstressed young male C57bl/6 and SV129 mice were compared, the SV129 mice had significantly reduced FS and EF yet had similar SERCA2a and NCX1 activity coupled to increased SER Ca 2ϩ content (32). The greater SER Ca 2ϩ content might have been predicted to result in better calcium release, especially at low SR load, and greater FS in the SV129 mice; however, this was not found.…”

Section: Discussionmentioning

confidence: 91%

“…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 evidence suggests that sex hormones are involved in regulating cardiac gene expression, modulate the response to cardiac stresses, and may play a protective role against calcium overload (5,31,32,33,35,36,2,15). Damage from ischemia-reperfusion has been linked to increased calcium.…”

mentioning

confidence: 99%

“…The available evidence suggests that sex hormones are involved in regulating cardiac gene expression, modulate the response to cardiac stresses, and may play a protective role against calcium overload (5,31,32,33,35,36,2,15). Damage from ischemia-reperfusion has been linked to increased calcium.…”

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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: Discussionmentioning

confidence: 91%

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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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“…Numerous parameters differ among healthy control mouse strains and may be determinants of their respective susceptibility to cardiac disease (5,6,15,22,34,36). They include gut microflora (15) and coronary vascular function (5) but also systemic metabolic parameters, such as blood glucose or insulin (6).…”

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confidence: 99%

“…They include gut microflora (15) and coronary vascular function (5) but also systemic metabolic parameters, such as blood glucose or insulin (6). Finally, more specifically at the cardiac level, studies have reported functional differences specifically in heart rate (HR) and left ventricular (LV) ejection fraction among various healthy control mouse strains, such as C57Bl/6 and SV129 (from Harlan, Oxfordshire, UK), both in vivo as well as ex vivo, during Langendorff perfusion in the presence of glucose as sole substrate (3,4,34). It is noteworthy, however, that these differences are generally of smaller magnitude than those reported following a stress challenge, both ex vivo (e.g., acute ischemia) and in vivo (e.g., acute hypoxia or aortic constriction) (3,4).…”

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confidence: 99%

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

Vaillant

Lauzier

Poirier

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism-a factor known to be closely related to function and contributes to disease development-is, however, unclear. This was examined in this study. In commonly used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J, and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3-mo-old working mouse hearts perfused ex vivo with physiological concentrations of 13C-labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7-fold vs. SJL/JCrNTac and C57Bl/6J; P < 0.05), whereas at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (∼−3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between 1) glycolysis, FA oxidation, and pyruvate metabolism and 2) cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.

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Strain‐specific modifier genes governing craniofacial phenotypes

Mukhopadhyay¹,

Brock²,

Webb³

et al. 2012

Birth Defects Research

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BACKGROUND The presence of strain-specific modifier genes is known to modulate the phenotype and pathophysiology of mice harboring genetically engineered mutations. Thus, identification of genetic modifier genes is requisite to understanding control of phenotypic expression. c-Ski is a transcriptional regulator. Ski−/− mice on a C57BL6J (B6) background exhibit facial clefting, while Ski−/− mice on a 129P3 (129) background present with exencephaly. METHODS In the present study, oligonucleotide-based gene expression profiling was utilized to identify potential strain-specific modifier gene candidates present in wild-type mice of B6 and 129 genetic backgrounds. Changes in gene expression were verified by TaqMan quantitative real-time PCR. RESULTS Steady-state levels of 89 genes demonstrated a significantly higher level of expression, and those of 68 genes demonstrated a significantly lower level of expression in the developing neural tubes from E8.5, B6 embryos when compared to expression levels in neural tubes derived from E8.5, 129 embryos. CONCLUSIONS Based on the results from the current comparative microarray study, and taking into consideration a number of relevant published reports, several potential strain-specific gene candidates, likely to modify the craniofacial phenotypes in various knockout mouse models have been identified.

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Genetic background affects function and intracellular calcium regulation of mouse hearts

Abstract: These results demonstrate that a different genetic background is associated with physiological differences in cardiac function in vivo and differences in morphology, contractility, and Ca(2+) handling at the cellular level.

Cited by 40 publications

References 38 publications

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

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

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

Strain‐specific modifier genes governing craniofacial phenotypes

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