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Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.

Awad S, Al-Haffar KM, Marashly Q, Quijada P, Kunhi M, Al-Yacoub N, Wade FS, Mohammed SF, Al-Dayel F, Sutherland G, Assiri A, Sussman M, Bers D, Al-Habeeb W, Poizat C - J. Pathol. (2014)

Bottom Line: Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood.Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3.The findings reveal a novel in vivo function of CaMKIIδ in regulating H3 phosphorylation and suggest a novel epigenetic mechanism by which CaMKIIδ controls cardiac hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Programme, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

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Increased p-H3 S10 in end-stage human heart failure and in rodent heart after pressure overload. (A) Immunoblot of control donor hearts (n = 4) and hearts of patients with end-stage heart failure (n = 4), showing increased p-H3 S10 in dilated human hearts. Consistent with the dilation phenotype, expression of CaMKIIδ, ANP, β-MHC, c-Myc and GATA-4 increased in failing hearts, whereas GAPDH and total H3 expression remained similar. (B) Quantitative analysis of (A); results are corrected for GAPDH and expressed as average ± SD; Student's t-test values are indicated. (C) Representative immunoblots, showing a progressive increase in p-H3 S10 after 10 days and 3 weeks of TAC in CaMKIIδ-WT hearts but not in CaMKIIδ-KO hearts. The hypertrophy marker proteins ANP, β-MHC c-Myc, GATA-4 and Mef2 are induced to different degrees in CaMKIIδ-WT mice subjected to TAC, but not in CaMKIIδ-KO mice after TAC. (D–J) Quantitative analysis of (C), performed in CaMKIIδ-WT and CaMKIIδ-KO mice after sham operation (n = 3) or TAC (n = 3). Values indicate expression of the indicated proteins ± SD, corrected for GAPDH. p values from Student's t-test are indicated
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fig01: Increased p-H3 S10 in end-stage human heart failure and in rodent heart after pressure overload. (A) Immunoblot of control donor hearts (n = 4) and hearts of patients with end-stage heart failure (n = 4), showing increased p-H3 S10 in dilated human hearts. Consistent with the dilation phenotype, expression of CaMKIIδ, ANP, β-MHC, c-Myc and GATA-4 increased in failing hearts, whereas GAPDH and total H3 expression remained similar. (B) Quantitative analysis of (A); results are corrected for GAPDH and expressed as average ± SD; Student's t-test values are indicated. (C) Representative immunoblots, showing a progressive increase in p-H3 S10 after 10 days and 3 weeks of TAC in CaMKIIδ-WT hearts but not in CaMKIIδ-KO hearts. The hypertrophy marker proteins ANP, β-MHC c-Myc, GATA-4 and Mef2 are induced to different degrees in CaMKIIδ-WT mice subjected to TAC, but not in CaMKIIδ-KO mice after TAC. (D–J) Quantitative analysis of (C), performed in CaMKIIδ-WT and CaMKIIδ-KO mice after sham operation (n = 3) or TAC (n = 3). Values indicate expression of the indicated proteins ± SD, corrected for GAPDH. p values from Student's t-test are indicated

Mentions: To assess H3 phosphorylation in the adult heart, we obtained samples from the left ventricle of control donor hearts and of patients in end-stage heart failure at the time of cardiac transplantation. Echocardiographic data showed cardiac dilatation and severely compromised cardiac function in patients with end-stage heart failure, with ejection fraction and fractional shortening averaging 16% and 9%, respectively (see supplementary material, Table S1, Figure S1A). Trichrome staining confirmed significant fibrosis in human failing hearts, whereas the hearts of normal individuals displayed almost no signs of pathology (see supplementary material, Figure S1B). Immunoblot analysis revealed a strong increase in p-H3 S10 in dilated human hearts compared to control hearts, which was paralleled by increased expression of CaMKIIδ (Figure 1A, B). As expected, heart failure markers, such as ANP and β-MHC, were up-regulated in failing hearts, whereas total H3 and GAPDH expression remained unchanged (Figure 1A, B). In addition, expression of GATA-4 and c-Myc, which are known to drive cardiac hypertrophy [26], were increased in human failing hearts (Figure 1A–J). Enhanced p-H3 S10 was also detected by indirect immunofluorescence (see supplementary material, Figure S2). Together, these results show a robust increase in p-H3S10 in end-stage human heart failure, associated with increased expression of hypertrophic gene markers as well as transcriptional activators driving cardiac hypertrophy.


Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress.

Awad S, Al-Haffar KM, Marashly Q, Quijada P, Kunhi M, Al-Yacoub N, Wade FS, Mohammed SF, Al-Dayel F, Sutherland G, Assiri A, Sussman M, Bers D, Al-Habeeb W, Poizat C - J. Pathol. (2014)

Increased p-H3 S10 in end-stage human heart failure and in rodent heart after pressure overload. (A) Immunoblot of control donor hearts (n = 4) and hearts of patients with end-stage heart failure (n = 4), showing increased p-H3 S10 in dilated human hearts. Consistent with the dilation phenotype, expression of CaMKIIδ, ANP, β-MHC, c-Myc and GATA-4 increased in failing hearts, whereas GAPDH and total H3 expression remained similar. (B) Quantitative analysis of (A); results are corrected for GAPDH and expressed as average ± SD; Student's t-test values are indicated. (C) Representative immunoblots, showing a progressive increase in p-H3 S10 after 10 days and 3 weeks of TAC in CaMKIIδ-WT hearts but not in CaMKIIδ-KO hearts. The hypertrophy marker proteins ANP, β-MHC c-Myc, GATA-4 and Mef2 are induced to different degrees in CaMKIIδ-WT mice subjected to TAC, but not in CaMKIIδ-KO mice after TAC. (D–J) Quantitative analysis of (C), performed in CaMKIIδ-WT and CaMKIIδ-KO mice after sham operation (n = 3) or TAC (n = 3). Values indicate expression of the indicated proteins ± SD, corrected for GAPDH. p values from Student's t-test are indicated
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383650&req=5

fig01: Increased p-H3 S10 in end-stage human heart failure and in rodent heart after pressure overload. (A) Immunoblot of control donor hearts (n = 4) and hearts of patients with end-stage heart failure (n = 4), showing increased p-H3 S10 in dilated human hearts. Consistent with the dilation phenotype, expression of CaMKIIδ, ANP, β-MHC, c-Myc and GATA-4 increased in failing hearts, whereas GAPDH and total H3 expression remained similar. (B) Quantitative analysis of (A); results are corrected for GAPDH and expressed as average ± SD; Student's t-test values are indicated. (C) Representative immunoblots, showing a progressive increase in p-H3 S10 after 10 days and 3 weeks of TAC in CaMKIIδ-WT hearts but not in CaMKIIδ-KO hearts. The hypertrophy marker proteins ANP, β-MHC c-Myc, GATA-4 and Mef2 are induced to different degrees in CaMKIIδ-WT mice subjected to TAC, but not in CaMKIIδ-KO mice after TAC. (D–J) Quantitative analysis of (C), performed in CaMKIIδ-WT and CaMKIIδ-KO mice after sham operation (n = 3) or TAC (n = 3). Values indicate expression of the indicated proteins ± SD, corrected for GAPDH. p values from Student's t-test are indicated
Mentions: To assess H3 phosphorylation in the adult heart, we obtained samples from the left ventricle of control donor hearts and of patients in end-stage heart failure at the time of cardiac transplantation. Echocardiographic data showed cardiac dilatation and severely compromised cardiac function in patients with end-stage heart failure, with ejection fraction and fractional shortening averaging 16% and 9%, respectively (see supplementary material, Table S1, Figure S1A). Trichrome staining confirmed significant fibrosis in human failing hearts, whereas the hearts of normal individuals displayed almost no signs of pathology (see supplementary material, Figure S1B). Immunoblot analysis revealed a strong increase in p-H3 S10 in dilated human hearts compared to control hearts, which was paralleled by increased expression of CaMKIIδ (Figure 1A, B). As expected, heart failure markers, such as ANP and β-MHC, were up-regulated in failing hearts, whereas total H3 and GAPDH expression remained unchanged (Figure 1A, B). In addition, expression of GATA-4 and c-Myc, which are known to drive cardiac hypertrophy [26], were increased in human failing hearts (Figure 1A–J). Enhanced p-H3 S10 was also detected by indirect immunofluorescence (see supplementary material, Figure S2). Together, these results show a robust increase in p-H3S10 in end-stage human heart failure, associated with increased expression of hypertrophic gene markers as well as transcriptional activators driving cardiac hypertrophy.

Bottom Line: Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood.Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3.The findings reveal a novel in vivo function of CaMKIIδ in regulating H3 phosphorylation and suggest a novel epigenetic mechanism by which CaMKIIδ controls cardiac hypertrophy.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Programme, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

Show MeSH
Related in: MedlinePlus