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Activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mTOR inhibition

PLoS ONE, ISSN: 1932-6203, Vol: 11, Issue: 11, Page: e0166839
2016
  • 17
    Citations
  • 0
    Usage
  • 27
    Captures
  • 0
    Mentions
  • 125
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    17
  • Captures
    27
  • Social Media
    125
    • Shares, Likes & Comments
      125
      • Facebook
        125

Article Description

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

Bibliographic Details

http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84996484153&origin=inward; http://dx.doi.org/10.1371/journal.pone.0166839; http://www.ncbi.nlm.nih.gov/pubmed/27880847; https://dx.plos.org/10.1371/journal.pone.0166839.g005; http://dx.doi.org/10.1371/journal.pone.0166839.g005; https://dx.plos.org/10.1371/journal.pone.0166839.g004; http://dx.doi.org/10.1371/journal.pone.0166839.g004; https://dx.plos.org/10.1371/journal.pone.0166839; https://dx.plos.org/10.1371/journal.pone.0166839.g003; http://dx.doi.org/10.1371/journal.pone.0166839.g003; https://dx.plos.org/10.1371/journal.pone.0166839.g001; http://dx.doi.org/10.1371/journal.pone.0166839.g001; https://dx.plos.org/10.1371/journal.pone.0166839.g002; http://dx.doi.org/10.1371/journal.pone.0166839.g002; https://dx.doi.org/10.1371/journal.pone.0166839.g003; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0166839.g003; https://dx.doi.org/10.1371/journal.pone.0166839.g004; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0166839.g004; https://dx.doi.org/10.1371/journal.pone.0166839.g002; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0166839.g002; https://dx.doi.org/10.1371/journal.pone.0166839; https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166839; https://dx.doi.org/10.1371/journal.pone.0166839.g005; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0166839.g005; https://dx.doi.org/10.1371/journal.pone.0166839.g001; https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0166839.g001; http://www.plosone.org/article/metrics/info:doi/10.1371/journal.pone.0166839; http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0166839&type=printable; http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166839; http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0166839; https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0166839&type=printable; http://dx.plos.org/10.1371/journal.pone.0166839.g005; http://dx.plos.org/10.1371/journal.pone.0166839.g003; http://dx.plos.org/10.1371/journal.pone.0166839.g004; http://dx.plos.org/10.1371/journal.pone.0166839.g001; http://dx.plos.org/10.1371/journal.pone.0166839.g002; http://dx.plos.org/10.1371/journal.pone.0166839

Ana Caroline Silva Freitas; Maria Jose Figueiredo; Erica Carolina Campos; Danilo Figueiredo Soave; Simone Gusmao Ramos; Herbert B. Tanowitz; Mara Rúbia N. Celes; Morris Karmazyn

Public Library of Science (PLoS)

Multidisciplinary

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