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June 26, 2019Scientific ReportsOpen Access

Mice with a knock-in mutation making CaMKIIδ resistant to reactive oxygen species activation (MMVV) exhibited significantly reduced myocardial death and improved left ventricular function 24 hours after ischemia-reperfusion injury compared to wild-type controls.

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Why the study?

ROS contribute to myocardial death during ischemia-reperfusion injury, but detailed knowledge of the molecular pathways connecting ROS to cardiac injury is lacking.

Population

Mice and isolated ventricular myocytes

Comparison

MMVV mice resistant to CaMKIIδ ROS activation vs WT controls

Design

In vivo and in vitro animal experiment

Follow-up

24 hours

Key result

Mice with a knock-in mutation making CaMKIIδ resistant to reactive oxygen species activation (MMVV) exhibited significantly reduced myocardial death and improved left ventricular function 24 hours after ischemia-reperfusion injury compared to wild-type controls.

Authors

YWYuejin WuQWQinchuan WangNFNing Feng

Discussion

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Overview

Ox-CaMKIIδ inhibition may confer cardioprotection; leaves open translation from mice to human ischemia-reperfusion injury.

Structured PICO

P
Population
Male wild-type and knock-in mutant mice (MMVV and T224A) subjected to in vivo and in vitro models of myocardial ischemia-reperfusion injury.
E
Exposure
Knock-in replacement of regulatory domain methionines with valines (MMVV) in CaMKIIδ or Kir6.2-T224A mutation, subjected to in vivo ischemia-reperfusion (45 minutes of ischemia followed by 24 hours of reperfusion) or in vitro simulated I/R and H2O2 exposure.
C
Comparator
Wild-type (WT) littermate control mice and their isolated ventricular myocytes subjected to the same in vivo or in vitro conditions.
O
Outcome
Myocardial death (area of necrosis/area at risk) and left ventricular function (ejection fraction, fractional shortening) 24 hours after I/R injury, and KATP current density.surrogate

Main Result

p-value: p=<0.05

Preventing CaMKIIδ oxidation protects against ischemia-reperfusion injury by preserving KATP channel current, identifying ox-CaMKII as a key mediator of ROS-induced myocardial death.

Limitations

  • Incomplete protection in MMVV mice suggests other ox-CaMKII independent pathways contribute to I/R injury.
  • Potential extramyocardial actions of ox-CaMKIIδ cannot be ruled out.
  • Animal and in vitro models may not fully translate to clinical I/R injury in humans.

Cite This Study

Wu et al. (2019) studied Myocardial ischemia-reperfusion injury. CaMKIIδ oxidation resistance (MMVV knock-in mutation) vs. Wild-type (WT) mice was evaluated on Myocardial death (Area of necrosis / Area at risk) after I/R injury (p=<0.05). Mice with a knock-in mutation making CaMKIIδ resistant to reactive oxygen species activation (MMVV) exhibited significantly reduced myocardial death and improved left ventricular function 24 hours after ischemia-reperfusion injury compared to wild-type controls.

synapsesocial.com/papers/6a8840ad8e586ad1c8a54b39https://doi.org/10.1038/s41598-019-45743-6
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