Jasmin Roohi1,2,3,4, Benjamin Kang1, David Bernard2, Djahida Bedja5, Harry C Dietz1,6, Lawrence C Brody7. 1. McKusick-Nathans Institute of Genetic Medicine and. 2. National Human Genome Research Institute, NIH, Bethesda, MD. 3. Division of Clinical Genetics, Columbia University School of Medicine, New York, NY. 4. Clinical Genetics, Kaiser Permanente Mid-Atlantic Permanente Medical Group, Rockville, MD. 5. Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD. 6. Howard Hughes Medical Institute, Baltimore, MD; and. 7. National Human Genome Research Institute, NIH, Bethesda, MD; lbrody@mail.nih.gov.
Abstract
Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA.Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Methods: Murine fibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Results: Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet.Conclusions:Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5-7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA.Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFSmouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Methods:Murinefibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Results:Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet.Conclusions:Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
Authors: S Dayal; T Bottiglieri; E Arning; N Maeda; M R Malinow; C D Sigmund; D D Heistad; F M Faraci; S R Lentz Journal: Circ Res Date: 2001-06-08 Impact factor: 17.367
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Authors: Rosina De Cario; Marco Giannini; Giulia Cassioli; Ada Kura; Anna Maria Gori; Rossella Marcucci; Stefano Nistri; Guglielmina Pepe; Betti Giusti; Elena Sticchi Journal: Diagnostics (Basel) Date: 2022-07-22