Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction

Grace M. Arteaga, Chad M. Warren, Sanja Milutinovic, Anne F. Martin, R. John Solaro

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca 2+ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice with a constitutive increase in myofilament Ca2+ sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD-57033, which acts specifically to enhance myofilament response to Ca2+. We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end-diastolic pressure was significantly elevated in nontransgenic (NTG) control hearts. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels. Ca2+- and cross bridge-dependent activation, protein breakdown, and phosphorylation in detergent-extracted fiber bundles were also investigated. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca2+-activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.

Original languageEnglish (US)
Pages (from-to)H2183-H2192
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number5 58-5
DOIs
StatePublished - Nov 1 2005

Keywords

  • Calcium sensitizers
  • Cross bridge-dependent activation
  • Phosphorylation
  • Stunning
  • Troponin I

ASJC Scopus subject areas

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

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