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

Objective-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 (PKC delta), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals. Methods and Results-Mouse experimental AAA is induced by perivascular administration of CaCl2. Mice deficient in PKC delta exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKC delta to the aortic wall of PKC delta(-/-) mice restores aneurysm, whereas overexpression of a dominant negative PKC delta mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKC delta(-/-) aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKC delta(-/-) mice restores inflammatory response and aneurysm development. Conclusion-PKC delta 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 PKC delta exacerbates the inflammatory process, in turn perpetuating elastin degradation and aneurysmal dilatation. Inhibition of PKC delta may serve as a potential therapeutic strategy for AAA. (Arterioscler Thromb Vasc Biol. 2012; 32: 2493-2502.)