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

Abstract

A bdominal aortic aneurysm (AAA), characterized by chronic aortic wall inflammation and destructive connective tissue remodeling, is one of the leading causes of sudden death in aging men (>55 years).1 Despite the current progress of surgical invasive repair or medical treatment, we lack a strategy to predict AAA rupture or to delay its progression. Epidemiological studies have identified several risk factors associated with AAA, including aging, male sex, smoking, and hypertension.1-3 However, the cause of AAA remains far from being fully elucidated. In This Issue, see p 1249Homocysteine (Hcy) is a sulfur-containing nonconstitutive amino acid derived from the essential amino acid methionine. The upper limit of the normal range for circulating Hcy is approximately 15 μmol/L, whereas a sex difference has been found, with approximately 10% to 15% higher levels in men versus women. Compelling evidence suggests that hyperhomocysteinemia (HHcy) is a strong independent risk factor of coronary heart disease and stroke in human.

Intermedin 1− 53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

“…The pathogenesis of AAA is possibly initiated by macrophage recruitment into the adventitia, then presentation in the media. 22 Various proinflammatory cytokines are secreted from the vessel cells to induce more inflammatory cells. 38 In the 2 AAA models, IMD successfully suppressed the protein expression of proinflammatory cytokines IL-6 and MCP-1.…”

“…8 Furthermore, we found similar effects of IMD on the mRNA expression of IL-6, MCP-1, and interferon-γ in aortic walls. Aortic adventitial fibroblasts may be involved in vascular wall inflammation and remodeling in AAA by transforming into α-actin-positive myofibroblasts and producing proinflammatory cytokines, 22 which, at least in part, was modulated by oxidative stress. 8,26 We found that IMD and antioxidant NAC both decreased the protein expression of IL-6, MCP-1, nuclear factor-κB, and tumor necrosis factor-α in adventitial fibroblasts, where proinflammatory cytokines are mainly observed in AAA according to our present and previous study.…”

“…8,26 We found that IMD and antioxidant NAC both decreased the protein expression of IL-6, MCP-1, nuclear factor-κB, and tumor necrosis factor-α in adventitial fibroblasts, where proinflammatory cytokines are mainly observed in AAA according to our present and previous study. 8,22 Pharmacological inhibition of oxidative stress has been reported to attenuate inflammation in AAA, 32,33,35 so the anti-inflammatory effect of IMD, at least in part, is mediated by inhibiting oxidative stress.…”

“…Then, we studied MCP-1 expression in the aortic wall because of their known role in macrophage migration and AAA formation. 22 MCP-1 was highly expressed in tunica media or adventitia, and its level was reduced by IMD 1−53 (Figure ⅢH in the online-only Data Supplement). To ascertain whether IMD attenuated vascular inflammation by inhibiting oxidative stress, NAC was used as a positive control in vitro.…”

Role of homocysteinylation of ACE in endothelial dysfunction of arteries

“…To date, several studies have suggested the existence of an interaction between Hcy and angiotensin II (ANG II) signaling as a pathway that contributes significantly to the potential oxidative stress in the vasculature (2,31). Some studies have addressed the possibility of ANG II signaling-related proteins, such as angiotensinconverting enzyme (ACE), serving as a target of Hcy (4,30,34). However, these studies reported general correlations between HHcy and ANG II/ACE signaling in different disease models.…”