Upregulation of Protein Kinase Cδ in Vascular Smooth Muscle Cells Promotes Inflammation in Abdominal Aortic Aneurysm

Ren

et al. 2015

Circulation Research

Self Cite

112

Rationale Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix (ECM) destruction and infiltration of inflammatory cells. Previous work with mouse models of AAA has shown that anti-inflammatory strategies can effectively attenuate aneurysm formation. Thrombospondin-1 (TSP1) is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of biological functions such as cell proliferation, apoptosis, and adhesion. Expression levels of TSP1 correlate with vascular disease conditions. Objective To use TSP1 deficient (Thbs1−/−) mice to test the hypothesis that TSP1 contributes to pathogenesis of AAAs. Methods and Results Mouse experimental AAA was induced either through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of Angiotensin II. Induction of AAA increased TSP1 expression in aortas of C57BL/6 or apoE−/− mice. Compared to Thbs1+/+ mice, Thbs1−/− mice developed significantly smaller aortic expansion when subjected to AAA inductions, which was associated with diminished infiltration of macrophages. Thbs1−/− monocytic cells had reduced adhesion and migratory capacity in vitro compared to wildtype counterparts. Adoptive transfer of Thbs1+/+ monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1−/− mice. Conclusions TSP1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development.

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Liu

Ren

et al. 2015

Circulation Research

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112

“…Prior studies including those from our own group have implicated PKC␦ in the regulatory pathway of CCL2 expression (18,19,33). Liu et al (50) suggested that PKC␦ mediates the stability of Ccl2 mRNA when VSMCs are treated with PDGF-BB or angiotensin II.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported a 2.51 Ϯ 0.24-fold increase in PKC␦ protein in VSMCs of aneurysmal arteries (18,33). To study the role of PKC␦ in chemokine expression by VSMCs, we mimicked this pathological PKC␦ up-regulation by overexpressing PKC␦ in cultured arterial VSMCs to a similar level (2.88 Ϯ 0.15-fold induction) (Fig.…”

Section: Pkc␦ Regulates Proinflammatory Chemokine Expression-mentioning

confidence: 94%

Protein Kinase C-δ (PKCδ) Regulates Proinflammatory Chemokine Expression through Cytosolic Interaction with the NF-κB Subunit p65 in Vascular Smooth Muscle Cells

Ren

Wang

Journal of Biological Chemistry

et al. 2014

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Background: Proinflammatory chemokines released by vascular smooth muscle cells (VSMCs) play a critical role in vascular inflammation. Results: Promoting protein kinase C-␦ (PKC␦) translocation or inhibition of NF-B pathway diminishes proinflammatory chemokine production. Conclusion: PKC␦ regulates proinflammatory chemokine expression through cytosolic interaction with the NF-B subunit p65, thus modulating inflammation. Significance: Learning how PKC␦ regulates proinflammatory chemokine expression is crucial for understanding vascular inflammation.

“…21 We have recently reported that protein kinase C-␦ mediates the expression of MCP-1 in vascular SMCs in response to another proinflammatory or apoptotic factor tumor necrosis factor-␣. 24 Protein kinase C-␦, a well-established mediator of apoptosis, 25,26 has also been found to be upregulated in human aneurysm tissues. 24 Whether protein kinase C-␦ is the molecular link between SMC apoptosis and the production of monocyte chemoattractants remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice

Yamanouchi

Kato

et al. 2010

ATVB

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Objective-The presence of apoptotic markers is a prominent histological feature of abdominal aortic aneurysm. To understand the role of apoptosis in the pathogenesis of this common vascular disease, we tested the effect of the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (Q-VD-OPh) on aneurysm formation using a mouse angiotensin II (Ang II) model. Methods and Results-Ang II in apolipoprotein E-deficient mice significantly induced medial cell apoptosis 3 days after infusion at the aortic region, eventually becoming aneurismal. A daily administration of 20 mg/kg per day Q-VD-OPh starting 6 hours before Ang II infusion reduced aneurysm incidence from 83.3% to 16.7% and maximal aortic diameter from 2.43Ϯ0.29 mm to 1.58Ϯ0.18 mm. The caspase inhibitor treated mice showed profoundly diminished levels of medial apoptosis and inflammation. In contrast, administration of Q-VD-OPh starting 7 days after Ang II infusion had no significant impact on aneurysm development. In vitro, media conditioned by Ang II-treated smooth muscle cells (SMCs) stimulated macrophage chemotaxis in a caspase-dependent manner. Inhibition of monocyte chemoattractant protein-1 (MCP-1) in the conditioned media via a neutralizing antibody completely blocked the ability of conditioned media to attract macrophages. Conclusion-These