| Property | Value |
|---|
| Working Groups |  AG Linke |
| Subproject | B03 |
| Open Access |  Yes |
| Publication Type | Journal Article |
| Peer Reviewed | Unknown |
| PMID |  23213108 |
| DOI |  10.1093/cvr/cvs353 |
| Publication Year | 2013 |
| Title | Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction  |
| Journal | Cardiovascular Research |
| ISSN | 0008-6363 |
| eISSN | 1755-3245 |
| URL | http://cardiovascres.oxfordjournals.org/content/97/3/464 |
| Pages | 464-471 |
| Issue | 3 |
| Volume | 97 |
| Journal Abbreviation | Cardiovasc Res |
| Extra | Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Key alterations in HFpEF include increased left ventricular (LV) stiffness and abnormal relaxation. We hypothesized that myofilament protein phosphorylation and function are deranged in experimental HFpEF vs . normal myocardium. Such alterations may involve the giant elastic protein titin, which contributes decisively to LV stiffness. Methods and results LV tissue samples were procured from normal dogs (CTRL) and old dogs with hypertension-induced LV hypertrophy and diastolic dysfunction (OHT/HFpEF). We quantified the expression and phosphorylation of myofilament proteins, including all-titin and site-specific titin phosphorylation, and assessed the expression/activity of major protein kinases (PKs) and phosphatases (PPs), myofilament calcium sensitivity (pCa50), and passive tension (Fpassive) of isolated permeabilized cardiomyocytes. In OHT vs . CTRL hearts, protein kinase-G (PKG) activity was decreased, whereas PKCα activity and PP1/PP2a expression were increased. Cardiac MyBPC, TnT, TnI and MLC2 were less phosphorylated and pCa50 was increased in OHT vs . CTRL. The titin N2BA (compliant) to N2B (stiff) isoform-expression ratio was lowered in OHT. Hypophosphorylation in OHT was detected for all-titin and at serines S4010/S4099 within titin-N2Bus, whereas S11878 within proline, glutamate, valine, and lysine (PEVK)-titin was hyperphosphorylated. Cardiomyocyte Fpassive was elevated in OHT, but could be normalized by PKG or PKA, but not PKCα, treatment. Conclusions This patient-mimicking HFpEF model is characterized by titin stiffening through altered isoform composition and phosphorylation, both contributing to increased LV stiffness. Hypophosphorylation of myofilament proteins and increased calcium sensitivity suggest that functional impairment at the sarcomere level may be an early event in HFpEF. PMID: 23213108 |
| Authors | Hamdani N, Bishu KG, von Frieling-Salewsky M, Redfield MM, Linke WA |
| First Author | Hamdani N |
| Last Author | Linke WA |
| Scholia |  Wikidata-based representation at Scholia |
External Resources
academic...53.pdfhttps://academic.oup.com/cardiovascres/article-pdf/97/3/464/17240193/cvs353.pdf
Article fulltext
gro-2/57641http://resolver.sub.uni-goettingen.de/purl?gro-2/57641
GRO.publications identifier
9615https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=9615
NCBI Taxonomy (Canis lupus familiaris)
0000-0003-0801-3773https://orcid.org/0000-0003-0801-3773
ORCID identifier (Wolfgang A. Linke)
academic...521323https://academic.oup.com/cardiovascres/article/97/3/464/276265#85521323
Supplemental material
SCR_003070https://scicrunch.org/resolver/SCR_003070
SciCrunch identifier (RRID:SCR_003070, ImageJ)
SCR_015807https://scicrunch.org/resolver/SCR_015807
SciCrunch identifier (RRID:SCR_015807, GraphPad Prism)
Q8WZ42https://www.uniprot.org/uniprot/Q8WZ42
UniProt identifier
Q48772970https://www.wikidata.org/wiki/Q48772970
Wikidata ID
