Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2/NF-κB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models

Abstract

Introduction

In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1−/−). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps.

Methods

Peli1fl/fl and Peli1−/− mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1−/− mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis.

Results

Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1−/− mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice.

Conclusion

These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.

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Acknowledgements

This study was supported by National Institutes of Health Grant GM112957 to N. Maulik.

Funding

This work was presented at the following meetings: (i) American Heart Scientific Sesson 2016 and the abstract was published in Circulation. (ii) American College of Surgeons Annual meeting 2015 and the abstract was published in Journal of American College of Surgeons. (iii) New England Surgical Society—22nd Annual Surgical Resident and Fellow Research Presentation Day, 2015

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Correspondence to Nilanjana Maulik.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Selvaraju, V., Thirunavukkarasu, M., Joshi, M. et al. Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2/NF-κB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models. Basic Res Cardiol 115, 45 (2020). https://doi.org/10.1007/s00395-020-0804-4

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Keywords

  • Myocardial infarction
  • cIAP2
  • Hindlimb ischemia
  • Angiogenesis
  • NF-κB