Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice.
BACKGROUND
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.


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 Hcy: 50% 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.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China .
Ziyi
Z
Liu
Hongzhi
H
Luo
Lu
L
Zhang
Yaqian
Y
Huang
Bo
B
Liu
Kongyang
K
Ma
Juan
J
Feng
Jinsheng
J
Xie
Jingang
J
Zheng
Jing
J
Hu
Siyan
S
Zhan
Yi
Y
Zhu
Qingbo
Q
Xu
Wei
W
Kong
Xian
X
Wang
D063194:Adventitia / Q000276:immunology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000453:epidemiology* / Q000276:immunology*; D001057:Apolipoproteins E / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000453:epidemiology* / Q000276:immunology* / Q000378:metabolism; D015994:Incidence; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000276:immunology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014657:Vasculitis / Q000453:epidemiology* / Q000276:immunology* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse