title: Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo.
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.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Lu
authors.initials: L
authors.lastname: Kang
authors.affiliation: Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota;
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hillestad
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.affiliation: Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; nath.karl@mayo.edu.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
mesh_terms: D063194:Adventitia / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics; D008297:Male; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D013314:Stress, Mechanical; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; D016328:NF-kappa B; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2
keywords: cytokines; heme oxygenase; inflammation; shear stress; vascular injury
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