Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo

Lu Kang, Matthew L. Hillestad, Joseph P. Grande, Anthony J. Croatt, Michael A. Barry, Gianrico Farrugia, Zvonimir S. Katusic, Karl A. Nath

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-κB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1+/+ and HO-1-/- mice, whereas HO-1 induction was exaggerated in HO-2+/+ mice compared with HO-2-/- mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno-associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-κB activation, and, along with induced HO-2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo.

Original languageEnglish (US)
Pages (from-to)H1402-H1413
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number11
DOIs
StatePublished - Jun 1 2015

Keywords

  • Cytokines
  • Heme oxygenase
  • Inflammation
  • Shear stress
  • Vascular injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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