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Abstract: FR-PO336

Dysregulation of a Pro-Inflammatory Signaling Pathway Exacerbates Vascular Calcification Induced by Saturated Fatty Acids

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Keenan, Audrey L., University of Colorado AMC, Aurora, Colorado, United States
  • Kohno, Shohei, University of Colorado Denver, Aurora, Colorado, United States
  • Shiozaki, Yuji, University of Colorado Denver, Aurora, Colorado, United States
  • Miyazaki-anzai, Shinobu, University of Colorado-Denver, Aurora, Colorado, United States
  • Miyazaki, Makoto, University of Colorado-Denver, Aurora, Colorado, United States
Background

Vascular calcification is closely associated with cardiovascular mortality in patients with chronic kidney disease (CKD). We previously reported that saturated fatty acids (SFAs) such as stearic acid promote osteoblastic differentiation and mineralization of vascular smooth muscle cells (VSMCs). We recently found that profound activation of aortic IKKb and NFkB-mediated inflammation occurs in mouse models of vascular calcification such as SMC-specific SCD1/2 knockout mice. However, the pathological relevance of a pro-inflammatory signaling pathway to SFA-mediated vascular calcification in CKD is unknown. In this study, we investigated the role of the IKKb-NFkB pathway in the development of vascular calcification induced by SFAs.

Methods

We generated several in vitro models of IKKb-NFkB pathway activation or suppression using a mouse VSMC line, including VSMCs overexpressing constitutively active IKKb (IKKbCA) and IkBa (IKKb deficient) VSMCs (IkBaKO). For in vivo study, we generated SMC-specific IKKb knockout mice by crossing IKKb floxed mice with an SMC-specific Cre transgenic mouse line, SMMHC-Cre(ER)T2, to generate SMC-IKKbKO mice.

Results

IKKbCA significantly increased levels of phosphorylated (active) p65, and reduced levels of IkBa protein, a negative regulator of NFkB, resulting in increased expression of NFkB target genes, including IL-6, MCP-1 and iNOS. Importantly, IKKb activation increased the matrix calcium of VSMCs. In addition to IKKbCA, IkBaKO significantly increased expression of NFkB target genes and matrix calcium induced by stearate treatment compared with wild type VSMCs. We next examined whether IKKb inhibition inhibits calcification of VSMCs. shIKKb inhibited stearate-induced up-regulation of NFkB target genes. Unexpectedly, however, IKKb knockdown significantly accelerated stearate-induced vascular calcification. Consistent with the in vitro study, SMC-IKKbKO mice had significantly larger calcified medial lesions under 5/6 nephrectomy.

Conclusion

This study suggests that the IKKb-NFkB pathway positively and negatively regulates mineralization of VSMCs.

Funding

  • NIDDK Support