Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction

Nazha Hamdani, Kalkidan G. Bishu, Marion Von Frieling-Salewsky, Margaret M. Redfield, Wolfgang A. Linke

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

AimsHeart 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 resultsLV 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 (F passive) of isolated permeabilized cardiomyocytes. In OHT vs. CTRL hearts, protein kinase-G (PKG) activity was decreased, whereas PKC 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 PKC, treatment.ConclusionsThis 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.

Original languageEnglish (US)
Pages (from-to)464-471
Number of pages8
JournalCardiovascular research
Volume97
Issue number3
DOIs
StatePublished - Mar 1 2013

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Keywords

  • Diastolic heart failure
  • Hypertrophy
  • Passive stiffness
  • Titin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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