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New Methods

A Cell-Based Phenotypic Assay to Identify Cardioprotective Agents

Stephanie Guo, Adam Olm-Shipman, Andrew Walters, William R. Urciuoli, Stefanie Devito, Sergiy M. Nadtochiy, Andrew P. Wojtovich, Paul S. Brookes
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https://doi.org/10.1161/CIRCRESAHA.111.263715
Circulation Research. 2012;CIRCRESAHA.111.263715
Originally published March 6, 2012
Stephanie Guo
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Adam Olm-Shipman
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Andrew Walters
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William R. Urciuoli
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Stefanie Devito
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Sergiy M. Nadtochiy
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Andrew P. Wojtovich
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Paul S. Brookes
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Abstract

Rationale: Tissue ischemia/reperfusion (IR) injury underlies several leading causes of death such as heart-attack and stroke. The lack of clinical therapies for IR injury may be partly due to the difficulty of adapting IR injury models to high-throughput screening (HTS).

Objective: To develop a model of IR injury that is both physiologically relevant and amenable to HTS.

Methods and Results: A microplate-based respirometry apparatus was used. Controlling gas flow in the plate head space, coupled with the instrument's mechanical systems, yielded a 24-well model of IR injury in which H9c2 cardiomyocytes were transiently trapped in a small volume, rendering them ischemic. After initial validation with known protective molecules, the model was used to screen a 2000-molecule library, with post-IR cell death as an end point. Po2 and pH monitoring in each well also afforded metabolic data. Ten protective, detrimental, and inert molecules from the screen were subsequently tested in a Langendorff-perfused heart model of IR injury, revealing strong correlations between the screening end point and both recovery of cardiac function (negative, r2=0.66) and infarct size (positive, r2=0.62). Relationships between the effects of added molecules on cellular bioenergetics and protection against IR injury were also studied.

Conclusions: This novel cell-based assay can predict either protective or detrimental effects on IR injury in the intact heart. Its application may help identify therapeutic or harmful molecules.

  • chemical screen
  • myocardial infarction
  • stroke
  • cell culture
  • metabolism
  • myocardial ischemia
  • library
  • Received January 5, 2012.
  • Revision received February 21, 2012.
  • Accepted February 24, 2012.
  • © 2012 American Heart Association, Inc.
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    A Cell-Based Phenotypic Assay to Identify Cardioprotective Agents
    Stephanie Guo, Adam Olm-Shipman, Andrew Walters, William R. Urciuoli, Stefanie Devito, Sergiy M. Nadtochiy, Andrew P. Wojtovich and Paul S. Brookes
    Circulation Research. 2012;CIRCRESAHA.111.263715, originally published March 6, 2012
    https://doi.org/10.1161/CIRCRESAHA.111.263715

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    A Cell-Based Phenotypic Assay to Identify Cardioprotective Agents
    Stephanie Guo, Adam Olm-Shipman, Andrew Walters, William R. Urciuoli, Stefanie Devito, Sergiy M. Nadtochiy, Andrew P. Wojtovich and Paul S. Brookes
    Circulation Research. 2012;CIRCRESAHA.111.263715, originally published March 6, 2012
    https://doi.org/10.1161/CIRCRESAHA.111.263715
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