Uncoupling of increased cellular oxidative stress and myocardial ischemia reperfusion injury by directed sarcolemma stabilization

Joshua J. Martindale, Joseph M. Metzger

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54 Scopus citations


Myocardial ischemia/reperfusion (I/R) injury is a major clinical problem leading to cardiac dysfunction and myocyte death. It is widely held that I/R causes damage to membrane phospholipids, and is a significant mechanism of cardiac I/R injury. Molecular dissection of sarcolemmal damage in I/R, however, has been difficult to address experimentally. We studied here cardiac I/R injury under conditions targeting gain- or loss-of sarcolemma integrity. To implement gain-in-sarcolemma integrity during I/R, synthetic copolymer-based sarcolemmal stabilizers (CSS), including Poloxamer 188 (P188), were used as a tool to directly stabilize the sarcolemma. Consistent with the hypothesis of sarcolemmal stabilization, cellular markers of necrosis and apoptosis evident in untreated myocytes were fully blocked in sarcolemma stabilized myocytes. Unexpectedly, sarcolemmal stabilization of adult cardiac myocytes did not affect the status of myocyte-generated oxidants or lipid peroxidation in two independent assays. We also investigated the loss of sarcolemmal integrity using two independent genetic mouse models, dystrophin-deficient mdx or dysferlin knockout (Dysf KO) mice. Both models of sarcolemmal loss-of-function were severely affected by I/R injury ex vivo, and this was lessened by CSS. In vivo studies also showed that infarct size was significantly reduced in CSS-treated hearts. Mechanistically, these findings support a model whereby I/R-mediated increased myocyte oxidative stress is uncoupled from myocyte injury. Because the sarcolemma stabilizers used here do not transit across the myocyte membrane this is evidence that intracellular targets of oxidants are not sufficiently altered to affect cell death when sarcolemma integrity is preserved by synthetic stabilizers. These findings, in turn, suggest that sarcolemma destabilization, and consequent Ca2+ mishandling, as a focal initiating mechanism underlying myocardial I/R injury.

Original languageEnglish (US)
Pages (from-to)26-37
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
StatePublished - Feb 2014

Bibliographical note

Funding Information:
We thank Dr. DeWayne Townsend, for the helpful discussions on membrane sealants in cardiac disease, Dr. Chris Glembotski and Dr. Michael Kyba for the critical reading of earlier versions of the manuscript, and Martina Maerz, for her technical support. This work was supported by grants from the NIH , the MDA , and the UMN OVPR to JMM and AHA to JJM. We thank the Lillehei Heart Institute for their continued support.


  • Dysferlin
  • Dystrophin
  • Ischemia
  • Membrane
  • Reperfusion
  • Sarcolemma


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