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

Stephanie Morgan1, Dai Yamanouchi, Calvin Harberg

  • 1Division of Vascular Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

Arteriosclerosis, Thrombosis, and Vascular Biology
|August 11, 2012
PubMed
Abstract

Insights

Protein kinase C-delta (PKCδ) drives abdominal aortic aneurysm (AAA) by promoting smooth muscle cell apoptosis and inflammation. Inhibiting PKCδ could be a therapeutic strategy for AAA.

Area of Science:

  • Cardiovascular Biology
  • Vascular Inflammation
  • Cell Death Pathways

Background:

  • Smooth muscle cell (SMC) apoptosis is a key feature in abdominal aortic aneurysm (AAA) pathogenesis.
  • SMC apoptosis has been previously linked to the stimulation of pro-inflammatory signaling in AAA models.

Purpose of the Study:

  • To investigate the role of protein kinase C-delta (PKCδ), a known apoptotic mediator, in AAA development.
  • To determine if PKCδ regulates SMC apoptosis and pro-inflammatory signals contributing to AAA pathogenesis.

Main Methods:

  • Induction of experimental AAA in mice using perivascular CaCl(2) administration.
  • Utilized PKCδ-deficient (PKCδ(-/-)) and wild-type mice, including aortic SMCs and dominant-negative PKCδ mutants.
  • Assessed aneurysmal expansion, SMC apoptosis, inflammation, and monocyte chemoattractant protein-1 (MCP-1) production.

Main Results:

  • PKCδ deficiency significantly reduced AAA expansion, SMC apoptosis, and inflammation compared to wild-type mice.
  • Restoration of PKCδ in deficient mice re-established aneurysm formation; dominant-negative PKCδ attenuated aneurysm in wild-type mice.
  • PKCδ(-/-) SMCs showed impaired MCP-1 production, which was restored by recombinant MCP-1, re-initiating inflammation and aneurysm.

Conclusions:

  • PKCδ is a critical mediator of SMC apoptosis and inflammation in a mouse model of AAA.
  • Upregulated PKCδ exacerbates AAA by increasing MCP-1 expression in SMCs, driving elastin degradation and dilatation.
  • Targeting PKCδ presents a potential therapeutic avenue for treating abdominal aortic aneurysms.

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