Enhanced proatherogenic responses in macrophages and vascular smooth muscle cells derived from diabetic db/db mice

Shu Iian Li, Marpadga A. Reddy, Qiangjun Cai, Li Meng, Hang Yuan, Linda Lanting, Rama Natarajan

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/+ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid-metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element-binding protein and nuclear factor-{kappa}B, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/+. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a "preactivated" and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis.

Original languageEnglish (US)
Pages (from-to)2611-2619
Number of pages9
JournalDiabetes
Volume55
Issue number9
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

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Keywords

  • AGE, advanced glycation end product
  • COX-2, cyclooxygenase-2
  • CREB, cAMP response element-binding protein
  • DME, Dulbecco's modified Eagle's
  • ELISA, enzyme-linked immunosorbent assay
  • ERK, extracellular signal-regulated kinase
  • IFN, interferon

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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