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Selective Inhibition of Vascular Smooth Muscle Cell Function by COVID-19 Antiviral Drugs: Impact of Heme Oxygenase-1

Kelly J Peyton1, Giovanna L Durante1, William Durante1

  • 1Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.

Antioxidants (Basel, Switzerland)
|August 28, 2025
PubMed

Insights

Remdesivir, an antiviral drug, inhibits vascular smooth muscle cell proliferation and migration by inducing heme oxygenase-1 (HO-1) via the Nrf2 pathway. This may help prevent COVID-19-related vascular complications.

Area of Science:

  • Cardiovascular Science
  • Virology
  • Pharmacology

Background:

  • COVID-19 is linked to cardiovascular complications and high mortality.
  • Aberrant vascular smooth muscle cell (SMC) function is implicated in COVID-19 vascular disease.
  • The direct effects of COVID-19 antivirals on SMCs remain unclear.

Purpose of the Study:

  • To investigate the impact of three approved COVID-19 antiviral drugs (remdesivir, molnupiravir, nirmatrelvir) on SMC function.
  • To determine if these antivirals affect SMC proliferation, DNA synthesis, migration, and viability.
  • To elucidate the molecular mechanisms underlying any observed effects of remdesivir on SMCs.

Main Methods:

  • Vascular smooth muscle cells were treated with remdesivir, molnupiravir, or nirmatrelvir.
  • Cell proliferation, DNA synthesis, migration, and viability assays were performed.
  • Heme oxygenase-1 (HO-1) expression and its signaling pathways (Nrf2) were analyzed.
  • Gene silencing and reporter assays were used to confirm molecular mechanisms.

Main Results:

  • Remdesivir inhibited SMC proliferation, DNA synthesis, and migration without affecting cell viability.
  • Molnupiravir and nirmatrelvir did not exhibit these effects.
  • Remdesivir induced HO-1 expression, mediated by the Nrf2 pathway.
  • Carbon monoxide and bilirubin, downstream products of HO-1, reversed the effects of remdesivir.

Conclusions:

  • Remdesivir's inhibition of SMC proliferation and migration is mediated by HO-1 induction through the Nrf2 pathway.
  • The generation of carbon monoxide and bilirubin contributes to remdesivir's vascular protective effects.
  • These findings suggest a potential role for remdesivir in preventing COVID-19-associated occlusive vascular disease.

Keywords:
COVID-19heme oxygenase-1migrationmolnupiravirnirmatrelvirproliferationremdesivirvascular smooth muscle

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