Hyperhomocysteinemia Exaggerates Adventitial Inflammation and Angiotensin II–Induced Abdominal Aortic Aneurysm in Mice
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 1,489 subjects and found a strong association of HHcy and AAA (odds ratio 7.39). Next, we used angiotensin II (Ang II)–infused male ApoE-/- mice and tested whether HHcy contributes to AAA etiology. Homocysteine (Hcy) supplement (1.8g/L) in drinking water resulted in mild HHcy. Intriguingly, HHcy greatly increased the incidence of Ang II–induced AAA and aortic dissection in ApoE-/- mice (vehicle vs. Hcy: 50% vs. 100%, P<0.05). Histology indicated HHcy markedly exaggerated aortic adventitial inflammation. Increased levels of proinflammatory IL-6 and MCP-1 were preferentially colocalized within adventitial fibroblasts in HHcy+AngII mice, which suggested the importance of adventitial fibroblasts activation in Hcy-aggravated AAA. Indeed, Hcy sequentially stimulated adventitial fibroblasts transformation into myofibroblasts, secretion of IL-6 and MCP-1 and consequent recruitment of monocytes/macrophages to adventitial fibroblasts, which was abolished by the NADPH oxidase inhibitor DPI. NADPH oxidase 4 (Nox4) but not other homologs of NADPH oxidase was significantly upregulated by Hcy in adventitial fibroblasts, whereas Nox4 siRNA silencing diminished Hcy-induced adventitial fibroblasts activation. Finally, folic acid supplement (0.071 μg/g/day) markedly reduced HHcy aggravated AngII–induced AAA formation in ApoE-/- mice.
Conclusions: HHcy may aggravate AAA formation at least partially via activating adventitial fibroblast Nox4.
- Received April 1, 2012.
- Accepted August 21, 2012.
- Copyright © 2012, American Heart Association