Elevated Protein Kinase C- Contributes to Aneurysm Pathogenesis Through Stimulation of Apoptosis and Inflammatory Signaling

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Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 08/2012; 32(10):2493-502. DOI: 10.1161/ATVBAHA.112.255661
Source: PubMed


Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals.
Mouse experimental AAA is induced by perivascular administration of CaCl(2). Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ(-/-) mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ(-/-) aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ(-/-) mice restores inflammatory response and aneurysm development.
PKCδ is an important signaling mediator for SMC apoptosis and inflammation in a mouse model of AAA. By stimulating monocyte chemoattractant protein-1 expression in aortic SMCs, upregulated PKCδ exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKCδ may serve as a potential therapeutic strategy for AAA.

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    • "In experimental AAAs, we showed MCP-1 upregulation and apoptosis to occur primarily, though not exclusively, in the medial layer during early time points following aneurysm induction. Moreover, we showed in vitro that apoptotic SMCs release MCP-1 in large quantity [15], [32]. A similar link between SMC apoptosis and the production of pro-inflammatory cytokines has also been reported in atherosclerosis. "
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