Objective-Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree.Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites. Methods and Results-We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1Ϫ/Ϫ, and MKP-1 Ϫ/Ϫ mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1. Key Words: apoptosis Ⅲ arterial endothelium Ⅲ atherosusceptibility Ⅲ c-Jun N-terminal kinase Ⅲ mitogen-activated protein kinase phosphatase-1 A therosclerosis is characterized by the accumulation of cells, lipids, and extracellular matrix in the wall of an artery, which can result in occlusion of the vessel lumen. It develops predominantly at branches and bends that are exposed to disturbed patterns of blood flow, whereas regions exposed to uniform flow are protected. [1][2][3][4] The molecular mechanism underlying the distinct spatial distribution of lesions is likely to involve apoptosis. Regions that are predisposed to atherosclerosis are characterized by relatively high rates of endothelial cell (EC) injury and turnover, [5][6][7] and apoptosis can be induced in cultured EC by the application of atheroprone flow patterns. 8,9 A causal relationship between apoptosis and atherosclerosis was established by enforcing expression of a proapoptotic molecule in arterial EC, which enhanced the accessibility of lipoproteins and leukocytes to arteries and initiated lesion formation in hypercholesterolemic mice. 10 In addition, focal endothelial apoptosis/injury in atherosclerotic lesions can, in turn, lead to endothelial denudation and exposure of a procoagulant vascular wall, a major cause of coronary thrombosis. 11,12 Several proatherogenic agents are known to induce EC apoptosis, including oxidized low-density lipoproteins, 13 reactive oxygen intermediaries (eg, H 2 O 2 14 ) and proinflammatory mediators (eg, lipopolysaccharide [LPS], 15 tumor necrosis factor [TNF]-␣ 16 ) by activating distinct signaling pathways that converge to cleave procaspase-3 into the active form of caspase-3. Cleaved caspase-3, in turn, executes apoptosis by activating numerous downs...