Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.

Matrix metalloproteinases (MMPs) are thought to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Using the mouse brachiocephalic artery model of plaque instability, we compared apolipoprotein E (apoE)͞MMP-3, apoE͞MMP-7, apoE͞MMP-9, and apoE͞MMP-12 double knockouts with their age-, strain-, and sex-matched apoE single knockout controls. Brachiocephalic artery plaques were significantly larger in apoE͞MMP-3 and apoE͞MMP-9 double knockouts than in controls. The number of buried fibrous layers was also significantly higher in the double knockouts, and both knockouts exhibited cellular compositional changes indicative of an unstable plaque phenotype. Conversely, lesion size and buried fibrous layers were reduced in apoE͞MMP-12 double knockouts compared with controls, and double knockouts had increased smooth muscle cell and reduced macrophage content in the plaque, indicative of a stable plaque phenotype. ApoE͞MMP-7 double knockout plaques contained significantly more smooth muscle cells than controls, but neither lesion size nor features of stability were altered in these animals. Hence, MMP-3 and MMP-9 appear normally to play protective roles, limiting plaque growth and promoting a stable plaque phenotype. MMP-12 supports lesion expansion and destabilization. MMP-7 has no effect on plaque growth or stability, although it is associated with reduced smooth muscle cell content in plaques. These data demonstrate that MMPs are directly involved in atherosclerotic plaque destabilization and clearly show that members of the MMP family have widely differing effects on atherogenesis.animal models ͉ atherosclerosis M atrix metalloproteinases (MMPs) are a group of Ͼ20 zinccontaining endopeptidases that are either secreted or expressed at the cell surface of all of the main vascular cell types. MMPs have overlapping specificities, but each can process at least one extracellular matrix component, and many nonmatrix substrates have also been described. Given this complexity it is not surprising that multiple roles for MMPs have been proposed, including regulation of cell migration, proliferation, and death. As a result, roles for MMPs in atherosclerotic plaque growth and fibrous cap formation have been suggested (1). On the other hand, the presence of elevated mRNA, protein, and activity levels of MMPs within atherosclerotic lesions, particularly at the shoulder regions of the fibrous cap (2-5), has led to the suggestion that they degrade strength-giving extracellular matrix components, including fibrillar collagens. By this mechanism MMPs could promote atherosclerotic plaque destabilization, the main cause of myocardial infarction in humans.Intervention studies in animal models have been used to investigate the potential roles of MMPs in cardiovascular disease. For example, inhibition of MMP activity by adenovirusmediated delivery of the gene for human tissue inhibitor of metalloproteinases (TIMP)-1 reduced lesion size in the aortic root of apolipoprotein E (apoE) knockout mice (6). H...

Hydrogen sensors from Pd‐functionalized multi‐layer graphene nanoribbon networks are fabricated. The fabrication method of these networks is simple, low cost, and scalable, and their high specific surface area facilitates efficient functionalization and gas adsorption. These networks show high sensitivity to hydrogen at parts‐per‐million concentration levels at room temperature with a fast response and recovery time.

Background-These studies examined the early time course of plaque development and destabilization in the brachiocephalic artery of the apolipoprotein E-knockout mouse, the effects of pravastatin thereon, and the effects of pravastatin on established unstable plaques. Methods and Results-Male apolipoprotein E-knockout mice were fed a high-fat, cholesterol-enriched diet from the age of 8 weeks. Animals were euthanized at 1-week intervals between 4 and 9 weeks of fat feeding. Acutely ruptured plaques were observed in the brachiocephalic arteries of 3% of animals up to and including 7 weeks of fat feeding but in 62% of animals after 8 weeks, which suggests that there is a sharp increase in the number of plaque ruptures at 8 weeks. These acute plaque ruptures then appear to heal and form buried fibrous caps; after 9 weeks of fat feeding, mice had 1.05Ϯ0.15 buried fibrous caps at a single site in the brachiocephalic artery. Pravastatin (40 mg/kg of body weight per day for 9 weeks; resultant plasma concentration 16Ϯ4 nmol/L) had no effect on plasma cholesterol concentration in fat-fed apolipoprotein E-knockout mice but reduced the number of buried fibrous caps by 43% (PϽ0.0001). In longer-term experiments, the delay of pravastatin treatment until unstable plaques had developed reduced the incidence of acute plaque rupture by 36% (PϽ0.0001). Conclusions-Plaque rupture occurs at high frequency in the brachiocephalic arteries of male apolipoprotein E-knockout mice after 8 weeks of fat feeding. Pravastatin treatment inhibits early plaque rupture and is also effective when begun after unstable plaques have developed.