Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

Roman N RODIONOV; Hayan DAYOUB; Gary L BAUMBACH; Frank M FARACI; Steven R LENTZ; Cynthia M LYNCH; Katina M WILSON; Jeff W STEVENS; Daryl J MURRY; Masumi KIMOTO; Erland ARNING; Teodoro BOTTIGLIERI; John P COOKE

doi:10.1161/CIRCRESAHA.109.200360

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Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

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Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

Roman N RODIONOV, Hayan DAYOUB, Gary L BAUMBACH, Frank M FARACI, Steven R LENTZ, Cynthia M LYNCH, Katina M WILSON, Jeff W STEVENS, Daryl J MURRY, Masumi KIMOTO, …

Circulation research, Vol.106(3), pp.551-558

2010

DOI: 10.1161/CIRCRESAHA.109.200360

PMCID: PMC2831416

PMID: 20019334

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Abstract

Rationale: Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA). Objective: Using mice transgenic for overexpression of the ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1), we tested the hypothesis that overexpression of DDAH1 protects from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia. Methods and results: Hyperhomocysteinemia was induced in DDAH1 transgenic (DDAH1 Tg) mice and wild-type littermates using a high methionine/low folate (HM/LF) diet. Plasma total homocysteine was elevated approximately 3-fold in both wild-type and DDAH1 Tg mice fed the HM/LF diet compared with the control diet (P<0.001). Plasma ADMA was approximately 40% lower in DDAH1 Tg mice compared with wild-type mice (P<0.001) irrespective of diet. Compared with the control diet, the HM/LF diet diminished endothelium-dependent dilation to 10 micromol/L acetylcholine in cerebral arterioles of both wild-type (12 + or - 2 versus 29 + or - 3%; P<0.001) and DDAH1 Tg (14 + or - 3 versus 28 + or - 2%; P<0.001) mice. Responses to 10 micromol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30 + or - 3 versus 45 + or - 5%; P<0.05) but not DDAH1 Tg mice (45 + or - 7 versus 48 + or - 6%). DDAH1 Tg mice also were protected from hypertrophy of cerebral arterioles (P<0.05) but not from accelerated carotid artery thrombosis induced by the HM/LF diet. Conclusions: Overexpression of DDAH1 protects from hyperhomocysteinemia-induced alterations in cerebral arteriolar structure and vascular muscle function.

Fundamental and applied biological sciences. Psychology

Biological and medical sciences

Vertebrates: cardiovascular system

Details

Title: Subtitle: Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia
Creators: Roman N RODIONOV - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Hayan DAYOUB - Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, United States
Gary L BAUMBACH - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Frank M FARACI - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Steven R LENTZ - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Cynthia M LYNCH - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States
Katina M WILSON - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, United States
Jeff W STEVENS - Department of Medicine III University Center for Vascular Medicine, Angiology Division, University Hospital Carl Gustav Carus, Technical University of Dresden, Germany
Daryl J MURRY - University of Iowa College of Pharmacy, Iowa City, United States
Masumi KIMOTO - Department of Nutritional Science Okayama Prefectural University, Japan
Erland ARNING - Baylor Institute of Metabolic Disease, Dallas, Tex, United States
Teodoro BOTTIGLIERI - Division of Cardiovascular Medicine Stanford University School of Medicine, Calif, United States
John P COOKE - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Resource Type: Journal article
Publication Details: Circulation research, Vol.106(3), pp.551-558
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
DOI: 10.1161/CIRCRESAHA.109.200360
PMID: 20019334
PMCID: PMC2831416
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 2010
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9984040377902771

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