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The role of eNOS phosphorylation in causing drug-induced vascular injury

Grainne A McMahon Tobin1, Jun Zhang1, David Goodwin1

  • 1Division of Applied Regulatory Science, CDER, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

Toxicologic Pathology
|April 8, 2014
PubMed

Insights

Phosphorylation of eNOS at S615 is linked to drug-induced vascular injury (DIVI). This study investigated eNOS phosphorylation across drug classes and species, finding a strong association with DIVI development.

Area of Science:

  • Pharmacology
  • Vascular Biology
  • Biochemistry

Background:

  • Endothelial nitric oxide synthase (eNOS) regulation is crucial in drug-induced vascular injury (DIVI).
  • Previous research implicated eNOS regulation in DIVI caused by phosphodiesterase 4 inhibitors (PDE4i).

Purpose of the Study:

  • To investigate eNOS phosphorylation at key regulatory sites in mesentery and aorta across different DIVI-inducing drug classes.
  • To compare these phosphorylation changes across species.
  • To correlate eNOS phosphorylation with vascular injury and serum nitrite levels.

Main Methods:

  • Examined eNOS phosphorylation at S615 in rat mesentery and aorta following CI-1044 administration.
  • Utilized immunoprecipitation to identify eNOS-associated upstream regulators.
  • Administered various DIVI-inducing drugs, alone or with SIN-1 (NO donor) or L-NAME (eNOS inhibitor), to rats.
  • Correlated eNOS phosphorylation levels with vascular injury scores and serum nitrite.
  • Compared findings using a species-specific adenosine agonist (CI-947) in rats and primates.

Main Results:

  • CI-1044 significantly elevated eNOS phosphorylation at S615 in rat mesentery (35-fold) compared to aorta (3-fold).
  • Upstream regulators of eNOS activation were found in signalosome complexes.
  • DIVI-inducing drugs altered serum nitrite levels and mesentery vascular injury scores.
  • eNOS phosphorylation at S615 showed a positive correlation with DIVI activity.
  • Similar phosphorylation patterns were observed in rats and primates with CI-947 treatment.

Conclusions:

  • eNOS phosphorylation, particularly at S615, is strongly associated with the development of drug-induced vascular injury.
  • The mesentery appears more sensitive to eNOS phosphorylation changes than the aorta in DIVI.
  • These findings highlight a conserved mechanism of DIVI across different drug classes and species.
Keywords:
animal modelsdrug developmentrisk identification.vascular system

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