MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation
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Case Western Reserve University School of Graduate Studies / OhioLINK
2016
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ndltd-OhioLink-oai-etd.ohiolink.edu-case14682596162021-08-03T06:37:20Z MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation Gresham, Ken Physiology Myocardial contraction and relaxation are tightly controlled process that involve thick and thin filament regulatory proteins, and these regulatory proteins provide rapid modulation of ventricular pressure development and relaxation. Myosin binding protein-C (MyBP-C) is a thick filament regulatory protein that modulates myocardial contraction and relaxation through phosphorylation of three Ser residues (Ser273, Ser282, and Ser302) that are differentially targeted by multiple signaling pathways and during cardiac stress. However, the role of individual MyBP-C Ser residues is not fully understand, and determining the role of phosphorylation at individual sites is made difficult because other sarcomeric regulatory proteins such as troponin I (TnI) are targeted for post-translational modification by the same pathways that target MyBP-C. Therefore, the purpose of this thesis was to determine the relative contributions of individual MyBP-C Ser residue phosphorylation in enhancing ventricular pressure development and relaxation. To achieve these goals, we used echocardiography and P-V loop analysis to study ventricular function during acute ß-adrenergic stimulation and during neurohormonal stress using chronic a- and ß-adrenergic stimulation. Transgenic (TG) mice with Ser to Ala mutations at individual MyBP-C residues (preventing phosphorylation) were generated, and ventricular pressure development and relaxation were examined before and after dobutamine administration in combination with existing mouse lines with complete MyBP-C and TnI phospho-ablation. Neurohormonal stress increased MyBP-C phosphorylation at all three Ser residues and accelerated pressure development and relaxation to enhance cardiac output. Acute ß-adrenergic stimulation enhanced ventricular contraction and relaxation through MyBP-C phosphorylation, while full ß-adrenergic mediated acceleration of pressure development and relaxation was possible without TnI phosphorylation. Individual MyBP-C Ser residue phospho-ablation did not produce dysfunction or pathological cardiac hypertrophy, and each residue was phosphorylated independent of the phosphorylation status of neighboring residues. Ser282 phospho-ablation blunted adrenergic reserve, but Ser302 phosphorylation was increased more by PKA treatment and was required to increase developed pressure following ß-adrenergic stimulation. Further, Ser273 phosphorylation accelerates ventricular pressure development and increases maximal systolic pressure in response to hypertensive signaling. These results demonstrate that individual MyBP-C residue phosphorylation enhances systolic pressure development through pathway-specific targeting, and individual residue phospho-ablation does not produce pathological cardiac dysfunction. 2016-09-13 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1468259616 http://rave.ohiolink.edu/etdc/view?acc_num=case1468259616 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Physiology |
| spellingShingle |
Physiology Gresham, Ken MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| author |
Gresham, Ken |
| author_facet |
Gresham, Ken |
| author_sort |
Gresham, Ken |
| title |
MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| title_short |
MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| title_full |
MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| title_fullStr |
MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| title_full_unstemmed |
MyBP-C Phosphorylation Regulates Ventricular Pressure Development and Relaxation |
| title_sort |
mybp-c phosphorylation regulates ventricular pressure development and relaxation |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2016 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1468259616 |
| work_keys_str_mv |
AT greshamken mybpcphosphorylationregulatesventricularpressuredevelopmentandrelaxation |
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1719440075230543872 |