Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling

Stephanie Morgan, Dai Yamanouchi, Calvin Harberg, Qiwei Wang, Melissa Keller, Yi Si, William Burlingham, Stephen Seedial, Justin Lengfeld, Bo Liu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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-δ (PKCδ), 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 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. CONCLUSION-: 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.

Original languageEnglish (US)
Pages (from-to)2493-2502
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number10
DOIs
StatePublished - Nov 2012

Keywords

  • aneurysms
  • apoptosis
  • inflammation
  • protein kinase C-δ
  • vascular biology

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