title: Elevated protein kinase C-δ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Vascular Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Morgan
authors.forename: Dai
authors.initials: D
authors.lastname: Yamanouchi
authors.forename: Calvin
authors.initials: C
authors.lastname: Harberg
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Wang
authors.forename: Melissa
authors.initials: M
authors.lastname: Keller
authors.forename: Yi
authors.initials: Y
authors.lastname: Si
authors.forename: William
authors.initials: W
authors.lastname: Burlingham
authors.forename: Stephen
authors.initials: S
authors.lastname: Seedial
authors.forename: Justin
authors.initials: J
authors.lastname: Lengfeld
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology*; D002122:Calcium Chloride / Q000009:adverse effects; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004549:Elastin; D051745:Protein Kinase C-delta; D002122:Calcium Chloride