Journal
ATHEROSCLEROSIS
Volume 197, Issue 2, Pages 504-514Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2007.02.023
Keywords
atherosclerosis; cytokine; infection; inflammation; Porphyromonas gingivalis
Funding
- NHLBI NIH HHS [R01 HL076801-04, R01 HL076801-01A1, R01 HL076801-02, R01 HL076801-03, R01 HL 76801, R01 HL076801] Funding Source: Medline
Ask authors/readers for more resources
Background: Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis. Methods and results: To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE(+/-)-IL-6(+/-) and ApoE(+/-)-IL-6(-/-) mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50 VI live Porphyromonas gingivalis (Pg.) (10(7) CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE(+/-)-IL-6(+/-) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-IL-6(-/-) mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE(+/-)-IL-6(-/-) mice were significantly higher than ApoE(+/-)-IL-6(-/-) mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE(+/-)-IL-6(-/-) mice compared to ApoE(+/-)-IL-6(-/-) mice, irrespective of diet or inoculation. Conclusion: The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available