The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts

Guohu Li, Peter Whittaker, Mu Yao, Robert A. Kloner, Karin Przyklenk

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Background: Emerging evidence suggests that gap junction-mediated intercellular transmission of ions, metabolites and/or second messengers may serve as important determinants of myocyte viability. Our aim was to determine, using isolated buffer-perfused mouse hearts, whether the cardioprotection achieved with ischemic preconditioning (PC) is due in part to: (i) disruption of cell-cell coupling (manifest as a loss in the primary gap junction protein, connexin 43 [Cx43]) and resultant impaired transmission of a 'death' messenger, or conversely, (ii) transfer of a humoral 'survival' factor via existing gap junctions. Methods: To explore the first possibility, we employed immunostaining to visualize and quantify Cx43 in hearts subjected to 2 1/2 min of PC ischemia or a matched control period. To test the converse corollary, we assessed the effect of heptanol - an agent well recognized to rapidly and reversibly uncouple gap junctions - on the reduction of infarct size (delineated by tetrazolium staining) achieved with PC. Results: We found no evidence of a deficit in Cx43 immunoreactive signal in response to the PC stimulus. Area of necrosis (AN) was, as expected, reduced in hearts that received PC ischemia vs. controls (31±3% vs. 40±3% of the left ventricle [LV]; P<.01). However, treatment with heptanol rendered PC ineffective in eliciting protection (AN/LV: 42±1%). Conclusions: Our results suggest that gap junction-mediated transfer of an as-yet unknown 'survival' factor - rather than disrupted transfer of a 'death messenger' - may play a role in the increased resistance to infarction conferred by antecedent PC ischemia in mouse heart.

Original languageEnglish
Pages (from-to)158-165
Number of pages8
JournalCardiovascular Pathology
Volume11
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Cardioprotection
  • Connexin 43
  • Gap junctions
  • Myocardial infarction
  • Myocardial ischemia

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