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Extracellular Ubiquitin(1-76) and Ubiquitin(1-74) Regulate Cardiac Fibroblast Proliferation

Edwin K Jackson1, Eric Mi1, Vladimir B Ritov1

  • 1From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA.

Hypertension (Dallas, Tex. : 1979)
|October 26, 2018
PubMed

Insights

Ubiquitin(1-76) unexpectedly antagonizes SDF-1α-induced cardiac fibroblast proliferation by converting to ubiquitin(1-74), a CXCR4 antagonist. IDE inhibitors may increase cardiac fibrosis risk, especially with DPP4 inhibitors or hypertension.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Fibrosis Research

Background:

  • Stromal cell-derived factor-1α (SDF-1α) stimulates cardiac fibroblast proliferation via CXCR4, with enhanced effects in spontaneously hypertensive rats.
  • Dipeptidyl peptidase 4 (DPP4) metabolizes SDF-1α, and its inhibition potentiates SDF-1α's effects.
  • Ubiquitin(1-76) was proposed as a potential CXCR4 agonist, similar to SDF-1α.

Purpose of the Study:

  • To investigate the effect of ubiquitin(1-76) on cardiac fibroblast proliferation.
  • To determine if ubiquitin(1-76) acts as a CXCR4 agonist or antagonist.
  • To explore the role of insulin-degrading enzyme (IDE) in ubiquitin(1-76) mediated effects and its implications in hypertension.

Main Methods:

  • Primary cardiac fibroblast cultures from spontaneously hypertensive and Wistar-Kyoto rats.
  • Treatment with SDF-1α, sitagliptin (DPP4 inhibitor), ubiquitin(1-76), ubiquitin(1-74), and 6bk (IDE inhibitor).
  • Assessment of cardiac fibroblast proliferation and IDE activity.

Main Results:

  • Ubiquitin(1-76) did not stimulate proliferation but antagonized SDF-1α/sitagliptin effects, more potently in hypertensive cells.
  • Insulin-degrading enzyme (IDE) converted ubiquitin(1-76) to ubiquitin(1-74), which was a potent antagonist of SDF-1α/sitagliptin.
  • Ubiquitin(1-74) antagonism was not blocked by 6bk and was >10-fold more potent than ubiquitin(1-76).
  • Neither ubiquitin form affected neuropeptide Y-induced proliferation, confirming CXCR4 specificity.
  • Cardiac fibroblasts expressed IDE, converting ubiquitin(1-76) to ubiquitin(1-74), with higher IDE activity in hypertensive cells.

Conclusions:

  • Extracellular ubiquitin(1-76) inhibits SDF-1α/sitagliptin-induced cardiac fibroblast proliferation through IDE-mediated conversion to ubiquitin(1-74), a CXCR4 antagonist.
  • Hypertension exacerbates this inhibitory effect due to increased IDE activity.
  • Inhibition of IDE, particularly in conjunction with DPP4 inhibitors or in hypertensive states, may elevate the risk of cardiac fibrosis.
Keywords:
CXCR4 receptorSDF-1αfibroblastshypertensionneuropeptide Yubiquitin

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