Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.
Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.
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DOI：
10.1161/atvbaha.112.255661
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Morgan S;Yamanouchi D;Harberg C;Wang Q;Keller M;Si Y;Burlingham W;Seedial S;Lengfeld J;Liu B
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-delta (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 CaCl2. Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared to wildtype littermates. Delivery of PKCδ to the aortic wall of PKCδ−/− mice restores aneurysm, while overexpression of a dominant negative PKCδ mutant in the aorta of wildtype mice attenuates aneurysm. In vitro, PKCδ−/− aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 (MCP-1) production. Ectopic administration of recombinant MCP-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 MCP-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.
