Hypertrophy and Heart Failure in Mice Overexpressing the Cardiac Sodium-Calcium Exchanger

Roos, Kenneth P.; Jordan, Maria C.; Fishbein, Michael C.; Ritter, Matthew R.; Friedlander, Martin; Chang, Helen C.; Rahgozar, Paymon; Han, Tian; Garcia, Alejandro J.; MacLellan, W. Robb; Ross, Robert S.; Philipson, Kenneth D.

doi:10.1016/j.cardfail.2007.01.004

Cited by 57 publications

(77 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We found significantly increased NCX1 protein in intact female hearts than male hearts. Differences in the cardiac phenotype of gene modified NCX1 male and female mice support the idea of a greater dependence on NCX1 for calcium extrusion in females than males (20,31). NCX1 Ϫ/Ϫ females are more likely than NCX1 Ϫ/Ϫ males to develop heart failure postpressure overload, and NCX1 Ϫ/Ϫ females are prone to heart failure postpartum.…”

Section: Discussionmentioning

confidence: 79%

“…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.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…However, in the MOD phenotype, expression of NCX‐1 was increased and phosphorylation of phospholamban at S16 was decreased relative to sham and the other phenotypes (Figure 6A). While LVEF was preserved in the MOD phenotype, increases in NCX‐1 and decreased phospholamban phosphorylation are characteristic of humans with and experimental models of overt systolic HF 25, 26, 27, 28, 29…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

show abstract

“…Interestingly, we did not observe a significant increase in NCX1 protein expression in Col4a3 Ϫ/Ϫ mice compared with WT. Because the NCX1 is an important regulator of [Ca 2ϩ ] i in cardiomyocytes and is increased during cardiac hypertrophy (28,40), future studies concerning the effects of FGF23 on the myocardium may be warranted.…”

Section: Discussionmentioning

confidence: 99%

FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy

Touchberry

Green

Tchikrizov

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

168

155

View full text Add to dashboard Cite

Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein content of cardiac muscle. In addition, FGFR1 and FGFR3 mRNA were the most abundantly expressed FGF receptors in cardiomyocytes, and the coreceptor ␣-klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3 Ϫ/Ϫ mice) that has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3 Ϫ/Ϫ hearts compared with wild type but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3 Ϫ/Ϫ hearts did show reduced fractional shortening (Ϫ17%) and ejection fraction (Ϫ11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca 2ϩ ([Ca 2ϩ ]i; F/Fo ϩ 86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip contractility (67%), which was inhibited by FGF receptor antagonism. We hypothesize that although FGF23 can acutely increase [Ca 2ϩ ]i, chronically this may lead to decreases in contractile function or stimulate cardiac hypertrophy, as observed with other stress hormones. In conclusion, FGF23 is a novel bone/heart endocrine factor and may be an important mediator of cardiac Ca 2ϩ regulation and contractile function during chronic kidney disease. fibroblast growth factor 23; pathological cardiac hypertrophy; chronic kidney disease; Col4a3; cardiac function; ␣-klotho FIBROBLAST GROWTH FACTOR 23 (FGF23) is a hormone released primarily by osteocytes (2, 4, 14, 38) that functions to regulate phosphate and vitamin D homeostasis through direct actions on the kidney and parathyroid (2). Although an endocrine axis has been established between bone and kidney, a new paradigm is emerging in which FGF23 could be important in establishing an endocrine axis between bone and heart. Circulating levels of FGF23 are markedly elevated 100-to 1,000-fold in patients with chronic kidney disease (CKD) (24, 31) and are independently associated with cardiovascular morbidity and mortality (8,22,26,34,35,48,52). Specifically, an association between left ventricular (LV) hypertrophy and serum FGF23 levels has been established in CKD patients (20,36,52).Nevertheless, despite strong associations between FGF23 and adverse outcomes, it remains relatively unknown whether FGF23 is simply a marker of cardiac disease risk or a direct mediator of cardiac pathology and cardiac performance. Only one study to date has analyzed the direct effects of FGF23 on the heart both in vitro and in vivo (13). This important work by Faul et al. (13) shows that FGF23 can directly induce hypertrophy in isolated neonatal cardiomyocytes as well as with intramyocardial FGF23 injections. These authors also demonstrated that a FGF receptor (FGF...

show abstract

Hypertrophy and Heart Failure in Mice Overexpressing the Cardiac Sodium-Calcium Exchanger

Cited by 57 publications

References 51 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

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy

Contact Info

Product

Resources

About