Hyperhomocysteinemia Exaggerates Adventitial Inflammation and Angiotensin II−Induced Abdominal Aortic Aneurysm in Mice

• Published in: Circulation research Vol. 111; no. 10; pp. 1261 - 1273
• Main Authors: Liu, Ziyi, Luo, Hongzhi, Zhang, Lu, Huang, Yaqian, Liu, Bo, Ma, Kongyang, Feng, Juan, Xie, Jinsheng, Zheng, Jingang, Hu, Jing, Zhan, Siyan, Zhu, Yi, Xu, Qingbo, Kong, Wei, Wang, Xian
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 26.10.2012; Lippincott Williams & Wilkins
• Subjects: Adventitia - immunology; Angiotensin II - pharmacology; Animals; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - epidemiology; Aortic Aneurysm, Abdominal - immunology; Apolipoproteins E - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chemokine CCL2 - secretion; Disease Models, Animal; Diseases of the aorta; Female; Fibroblasts - enzymology; Fibroblasts - immunology; Fibroblasts - secretion; Fundamental and applied biological sciences. Psychology; Humans; Hyperhomocysteinemia - epidemiology; Hyperhomocysteinemia - immunology; Hyperhomocysteinemia - metabolism; Incidence; Interleukin-6 - secretion; Male; Medical sciences; Mice; Mice, Mutant Strains; Middle Aged; NADPH Oxidase 4; NADPH Oxidases - metabolism; Reactive Oxygen Species - metabolism; Risk Factors; Signal Transduction - immunology; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Vasculitis - epidemiology; Vasculitis - immunology; Vasculitis - metabolism; Vasoconstrictor Agents - pharmacology; Vertebrates: cardiovascular system; NADPH; Enzyme; Peptide hormone; Rodentia; Oxidase; Cardiovascular disease; Inflammation; Aortic aneurysm; abdominal aortic aneurysm; Octapeptide; Renin angiotensin system; Vertebrata; adventitial fibroblast; Mammalia; Mouse; NADPH oxidase 4; Hyperhomocysteinemia; Oxidoreductases; Circulatory system; Angiotensin II; Fibroblast
• DOI: 10.1161/CIRCRESAHA.112.270520
• ISSN: 0009-7330; 1524-4571

RATIONALE:A number of epidemiological studies have suggested an association of hyperhomocysteinemia (HHcy) and abdominal aortic aneurysm (AAA), but discrepancies exist. In addition, we lack direct evidence supporting a causal role. OBJECTIVE:We determined the association and contribution of HHcy to AAA formation. METHODS AND RESULTS:We first performed a meta-analysis of studies involving 1489 subjects and found a strong association of HHcy and AAA (odds ratio, 7.39). Next, we used angiotensin II–infused male apolipoprotein E–deficient mice and tested whether HHcy contributes to AAA pathogenesis. Homocysteine (Hcy) supplement (1.8 g/L) in drinking water resulted in mild HHcy. Intriguingly, HHcy greatly increased the incidence of angiotensin II–induced AAA and aortic dissection in apolipoprotein E–deficient mice (vehicle versus Hcy50% versus 100%; P<0.05). Histology indicated HHcy markedly exaggerated aortic adventitial inflammation. Increased levels of proinflammatory interleukin-6 and monocyte chemoattractant protein-1 were preferentially colocalized within adventitial fibroblasts in HHcy plus angiotensin II mice, which suggested the importance of adventitial fibroblasts activation in Hcy-aggravated AAA. Hcy sequentially stimulated adventitial fibroblasts transformation into myofibroblasts, secretion of interleukin-6 and monocyte chemoattractant protein-1, and consequent recruitment of monocytes/macrophages to adventitial fibroblasts, which was abolished by the NADPH oxidase inhibitor diphenyliodonium. NADPH oxidase 4, but not other homologs of NADPH oxidase, was significantly upregulated by Hcy in adventitial fibroblasts, whereas NADPH oxidase 4 small interfering RNA silencing diminished Hcy-induced adventitial fibroblasts activation. Finally, folic acid supplement (0.071 μg/g per day) markedly reduced HHcy-aggravated angiotensin II–induced AAA formation in apolipoprotein E–deficient mice. CONCLUSIONS:HHcy may aggravate AAA formation at least partially via activating adventitial fibroblast NADPH oxidase 4.