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Cardiac myosin binding protein C phosphorylation in cardiac disease.

Kuster DW, Bawazeer AC, Zaremba R, Goebel M, Boontje NM, van der Velden J - J. Muscle Res. Cell. Motil. (2011)

Bottom Line: Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart.Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease.In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands. d.kuster@vumc.nl

ABSTRACT
Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart. Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease. In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3. Moreover, we will discuss assays which allow to distinguish between functional consequences of mutant sarcomeric proteins and (mal)adaptive changes in sarcomeric protein phosphorylation.

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Cardiac MyBP-C phosphorylation in FHCM. a Phosphorylation status of cMyBP-C and cTnI was assessed by ProQ Diamond stained gels and signal was normalized to the SYPRO Ruby stained cMyBP-C and α-actinin band respectively as described before (Zaremba et al. 2007). Phosphorylation status of cMyBP-C and cTnI was lower in cardiac tissue obtained from myectomy operation from FHCM patients (NYHA class II) and in cardiac tissue obtained from explanted hearts from end-stage FHCM patients (NYHA class IV) compared to donor samples. Phosphorylation in the groups was normalized to donor, which was set to one. b In a subgroup of FHCM patients with MYBPC3 mutations (MYBPC3mut), the phosphorylation status of cMyBP-C was similar between FHCM and donor samples, while cTnI phosphorylation was lower. Phosphorylation was normalized to donor, which was set to one. *P < 0.05 versus donor in one-way ANOVA followed by post-test Bonferroni analysis. Figure adapted from van Dijk et al. (2009a) with permission
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Fig2: Cardiac MyBP-C phosphorylation in FHCM. a Phosphorylation status of cMyBP-C and cTnI was assessed by ProQ Diamond stained gels and signal was normalized to the SYPRO Ruby stained cMyBP-C and α-actinin band respectively as described before (Zaremba et al. 2007). Phosphorylation status of cMyBP-C and cTnI was lower in cardiac tissue obtained from myectomy operation from FHCM patients (NYHA class II) and in cardiac tissue obtained from explanted hearts from end-stage FHCM patients (NYHA class IV) compared to donor samples. Phosphorylation in the groups was normalized to donor, which was set to one. b In a subgroup of FHCM patients with MYBPC3 mutations (MYBPC3mut), the phosphorylation status of cMyBP-C was similar between FHCM and donor samples, while cTnI phosphorylation was lower. Phosphorylation was normalized to donor, which was set to one. *P < 0.05 versus donor in one-way ANOVA followed by post-test Bonferroni analysis. Figure adapted from van Dijk et al. (2009a) with permission

Mentions: The sarcomeric phosphorylation pattern in HCM shows a great deal of overlap with that in heart failure. Similar to heart failure samples, phosphorylation of cTnI was found to be reduced in FHCM (Hoskins et al. 2010; van Dijk et al. 2008; van Dijk et al. 2009b). Cardiac MyBP-C phosphorylation was also lower in FHCM patients (Hoskins et al. 2010; Jacques et al. 2008; van Dijk et al. 2008; van Dijk et al. 2009b), and Copeland et al. (2010) showed a shift towards unphosphorylated and mono-phosphorylated cMyBP-C similar to end-stage failing myocardium. The lower cMyBP-C phosphorylation in FHCM hearts was found in patients in whom no mutation was found in the genes coding for cMyBP-C, β-myosin heavy chain and troponin T. Figure 2a shows protein data from patients (NYHA class II) who underwent myectomy surgery to restore left ventricular outflow and from explanted heart samples of end-stage failing FHCM patients. In the Netherlands two founder mutations in MYBPC3 account for 35% of all HCM mutations (Alders et al. 2003). Although these mutations are predicted to result in truncated proteins, no mutant protein was found, indicating haplo insufficiency rather than a toxic peptide as the cause of FHCM (van Dijk et al. 2009a). In this patient population cMyBP-C protein levels were 33% lower than donor levels, but surprisingly relative phosphorylation of cMyBP-C was not different between patients and donors, whereas cTnI phosphorylation was notably reduced (van Dijk et al. 2009a) (Fig. 2b). The observation that cMyBP-C phosphorylation was similar in patients with MYBPC3 mutations compared to donors may be explained by an altered stoichiometry between kinase activities in the cardiac cells and cMyBP-C protein levels. The reduction in cMyBP-C protein level may match the reduction in kinase activities in FHCM with MYBPC3 mutations.Fig. 2


Cardiac myosin binding protein C phosphorylation in cardiac disease.

Kuster DW, Bawazeer AC, Zaremba R, Goebel M, Boontje NM, van der Velden J - J. Muscle Res. Cell. Motil. (2011)

Cardiac MyBP-C phosphorylation in FHCM. a Phosphorylation status of cMyBP-C and cTnI was assessed by ProQ Diamond stained gels and signal was normalized to the SYPRO Ruby stained cMyBP-C and α-actinin band respectively as described before (Zaremba et al. 2007). Phosphorylation status of cMyBP-C and cTnI was lower in cardiac tissue obtained from myectomy operation from FHCM patients (NYHA class II) and in cardiac tissue obtained from explanted hearts from end-stage FHCM patients (NYHA class IV) compared to donor samples. Phosphorylation in the groups was normalized to donor, which was set to one. b In a subgroup of FHCM patients with MYBPC3 mutations (MYBPC3mut), the phosphorylation status of cMyBP-C was similar between FHCM and donor samples, while cTnI phosphorylation was lower. Phosphorylation was normalized to donor, which was set to one. *P < 0.05 versus donor in one-way ANOVA followed by post-test Bonferroni analysis. Figure adapted from van Dijk et al. (2009a) with permission
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Related In: Results  -  Collection

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Fig2: Cardiac MyBP-C phosphorylation in FHCM. a Phosphorylation status of cMyBP-C and cTnI was assessed by ProQ Diamond stained gels and signal was normalized to the SYPRO Ruby stained cMyBP-C and α-actinin band respectively as described before (Zaremba et al. 2007). Phosphorylation status of cMyBP-C and cTnI was lower in cardiac tissue obtained from myectomy operation from FHCM patients (NYHA class II) and in cardiac tissue obtained from explanted hearts from end-stage FHCM patients (NYHA class IV) compared to donor samples. Phosphorylation in the groups was normalized to donor, which was set to one. b In a subgroup of FHCM patients with MYBPC3 mutations (MYBPC3mut), the phosphorylation status of cMyBP-C was similar between FHCM and donor samples, while cTnI phosphorylation was lower. Phosphorylation was normalized to donor, which was set to one. *P < 0.05 versus donor in one-way ANOVA followed by post-test Bonferroni analysis. Figure adapted from van Dijk et al. (2009a) with permission
Mentions: The sarcomeric phosphorylation pattern in HCM shows a great deal of overlap with that in heart failure. Similar to heart failure samples, phosphorylation of cTnI was found to be reduced in FHCM (Hoskins et al. 2010; van Dijk et al. 2008; van Dijk et al. 2009b). Cardiac MyBP-C phosphorylation was also lower in FHCM patients (Hoskins et al. 2010; Jacques et al. 2008; van Dijk et al. 2008; van Dijk et al. 2009b), and Copeland et al. (2010) showed a shift towards unphosphorylated and mono-phosphorylated cMyBP-C similar to end-stage failing myocardium. The lower cMyBP-C phosphorylation in FHCM hearts was found in patients in whom no mutation was found in the genes coding for cMyBP-C, β-myosin heavy chain and troponin T. Figure 2a shows protein data from patients (NYHA class II) who underwent myectomy surgery to restore left ventricular outflow and from explanted heart samples of end-stage failing FHCM patients. In the Netherlands two founder mutations in MYBPC3 account for 35% of all HCM mutations (Alders et al. 2003). Although these mutations are predicted to result in truncated proteins, no mutant protein was found, indicating haplo insufficiency rather than a toxic peptide as the cause of FHCM (van Dijk et al. 2009a). In this patient population cMyBP-C protein levels were 33% lower than donor levels, but surprisingly relative phosphorylation of cMyBP-C was not different between patients and donors, whereas cTnI phosphorylation was notably reduced (van Dijk et al. 2009a) (Fig. 2b). The observation that cMyBP-C phosphorylation was similar in patients with MYBPC3 mutations compared to donors may be explained by an altered stoichiometry between kinase activities in the cardiac cells and cMyBP-C protein levels. The reduction in cMyBP-C protein level may match the reduction in kinase activities in FHCM with MYBPC3 mutations.Fig. 2

Bottom Line: Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart.Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease.In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands. d.kuster@vumc.nl

ABSTRACT
Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart. Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease. In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3. Moreover, we will discuss assays which allow to distinguish between functional consequences of mutant sarcomeric proteins and (mal)adaptive changes in sarcomeric protein phosphorylation.

Show MeSH
Related in: MedlinePlus