| pubmed-article:18802026 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C0232164 | lld:lifeskim |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C0031715 | lld:lifeskim |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C0010531 | lld:lifeskim |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C1417523 | lld:lifeskim |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C0022702 | lld:lifeskim |
| pubmed-article:18802026 | lifeskim:mentions | umls-concept:C0000894 | lld:lifeskim |
| pubmed-article:18802026 | pubmed:issue | 9 | lld:pubmed |
| pubmed-article:18802026 | pubmed:dateCreated | 2008-10-24 | lld:pubmed |
| pubmed-article:18802026 | pubmed:abstractText | Normal cardiac function requires dynamic modulation of contraction. beta1-adrenergic-induced protein kinase (PK)A phosphorylation of cardiac myosin binding protein (cMyBP)-C may regulate crossbridge kinetics to modulate contraction. We tested this idea with mechanical measurements and echocardiography in a mouse model lacking 3 PKA sites on cMyBP-C, ie, cMyBP-C(t3SA). We developed the model by transgenic expression of mutant cMyBP-C with Ser-to-Ala mutations on the cMyBP-C knockout background. Western blots, immunofluorescence, and in vitro phosphorylation combined to show that non-PKA-phosphorylatable cMyBP-C expressed at 74% compared to normal wild-type (WT) and was correctly positioned in the sarcomeres. Similar expression of WT cMyBP-C at 72% served as control, ie, cMyBP-C(tWT). Skinned myocardium responded to stretch with an immediate increase in force, followed by a transient relaxation of force and finally a delayed development of force, ie, stretch activation. The rate constants of relaxation, k(rel) (s-1), and delayed force development, k(df) (s-1), in the stretch activation response are indicators of crossbridge cycling kinetics. cMyBP-C(t3SA) myocardium had baseline k(rel) and k(df) similar to WT myocardium, but, unlike WT, k(rel) and k(df) were not accelerated by PKA treatment. Reduced dobutamine augmentation of systolic function in cMyBP-C(t3SA) hearts during echocardiography corroborated the stretch activation findings. Furthermore, cMyBP-C(t3SA) hearts exhibited basal echocardiographic findings of systolic dysfunction, diastolic dysfunction, and hypertrophy. Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction. | lld:pubmed |
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| pubmed-article:18802026 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:18802026 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18802026 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18802026 | pubmed:month | Oct | lld:pubmed |
| pubmed-article:18802026 | pubmed:issn | 1524-4571 | lld:pubmed |
| pubmed-article:18802026 | pubmed:author | pubmed-author:MossRichard... | lld:pubmed |
| pubmed-article:18802026 | pubmed:author | pubmed-author:GreaserMarion... | lld:pubmed |
| pubmed-article:18802026 | pubmed:author | pubmed-author:PowersPatrici... | lld:pubmed |
| pubmed-article:18802026 | pubmed:author | pubmed-author:StelzerJulian... | lld:pubmed |
| pubmed-article:18802026 | pubmed:author | pubmed-author:TongCarl WCW | lld:pubmed |
| pubmed-article:18802026 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:18802026 | pubmed:day | 24 | lld:pubmed |
| pubmed-article:18802026 | pubmed:volume | 103 | lld:pubmed |
| pubmed-article:18802026 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18802026 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18802026 | pubmed:pagination | 974-82 | lld:pubmed |
| pubmed-article:18802026 | pubmed:dateRevised | 2010-9-21 | lld:pubmed |
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