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he pivotal role of chronic inflammation in the pathogen- esis of atherosclerosis and aortic aneurysm is now firmly established.1 Atherosclerotic lesions usually develop at branch points in arteries with abnormal shear stress. Risk factors such as hypercholesterolemia, hypertension, and ciga- rette smoke, among others, promote injury to the vascular endothelium, resulting in the infiltration of leukocytes to initiate an inflammatory response. Monocytes infiltrating the lesion area accumulate lipids and become foam cells. Meanwhile, T lym- phocytes populating the intimal area of the lesion secrete inflammatory cytokines such as -interferon (INF) and tumor necrosis factors (TNF) that further stimulate macrophages and activate vascular endothelial and smooth muscle cells. Chronic inflammation of the vessel wall attributable to repetitive endo- thelial injury advances lesion development with the deposition of extracellular matrix in forming a fibrous cap. See page 1760 The coordinated regulation of extracellular matrix synthesis and degradation is essential for the maintenance of vascular ho- meostasis and plaque stability. Matrix metalloproteinases (MMPs) that degrade extracellular matrix promote atheroscle- rotic lesion formation by increasing smooth muscle cell migra- tion and angiogenesis. Lesions with thin fibrous cap covering a necrotic core of dead cells are prone to fissures and rupture resulting in myocardial infarction. Likewise, the increase in MMP activities in the abdominal aorta also leads to the devel- opment of abdominal aortic aneurysm (AAA) and rupture.2,3 Stimuli that have been linked to inflammation and atherosclero- sis are also observed in AAA, suggesting that these 2 vascular disease processes may have similar etiology and progression. In the past 2 years, several studies have reported the partici- pation of the stress responsive c-Jun N-terminal kinase (JNK) signaling cascade in atherosclerosis and AAA. First, JNK activity was shown to be elevated in atherosclerotic lesion areas4,5 and that JNK2 gene inactivation significantly decreased atherosclerosis in mice.4 Second, JNK2 was activated when macrophages were exposed to oxidized LDL.6 Importantly, JNK blockade inhibited both scavenger receptor A- and CD36- mediated modified LDL uptake, foam cell formation, and atherogenesis in mice.4,6 These latter studies suggested that JNK inhibition may be a potential target to reduce atherosclerosis, at least during the early stages of lesion development. Studies have also implicated a role of JNK in extracellular matrix homeostasis in the vasculature. In an elegant study reported by Yoshimura toward the end of 2005,7 phosphorylated JNK2 was found to be expressed in abundance in human AAA walls and colocalized with MMP. These investigators further demonstrated in 2 mouse models that suppression of JNK activity can lead to AAA regression. Using primary rat aortic smooth muscle cells in culture, these investigators showed that JNK activation induces a proinflammatory signaling cascade. Genes important for extracellular matrix degradation such as MMP-9 and the MMP-9 activator lipocalin-2 are also highly expressed on JNK activation. In contrast, genes that participate in matrix biosynthesis, including lysyl hydroxylase, lysyl oxi- dase, and prolyl 4-hydroxylase are suppressed by JNK activa- tion.7 The mechanism by which JNK activation modulates the expression of genes regulating extracellular matrix biosynthesis and degradation has not been defined.

A No-No for NonO and JNK in Extracellular Matrix Homeostasis and Vascular Stability