Abstract P128: RhoBTB1, a Novel PPARγ Target Gene Regulates Vascular Function
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. We previously reported that mice (S-DN) expressing a dominant-negative PPARγ mutation in smooth muscle cells (SMC) are hypertensive, exhibit impaired vascular relaxation and enhanced contraction, and display reduced expression of a novel PPARγ target gene, RhoBTB1. We hypothesized that RhoBTB1 may play a role in the PPARγ-mediated regulation of vascular function that is disrupted in S-DN mice. To test this, we generated transgenic mice (R+) with tamoxifen-inducible, Cre-dependent expression of RhoBTB1 in SMC. These mice were crossed with S-DN to produce mice (S-DN/R+) in which tamoxifen-treatment (75 mg/kg, ip, for 5 days) increased RhoBTB1 RNA expression in aorta from the reduced level seen in S-DN mice, and restored it to the level of non-transgenic mice. Thoracic aorta from S-DN showed impaired acetylcholine (ACh)-induced endothelial-dependent relaxation, which was reversed by replacement of RhoBTB1 in SMC (43.3±4.4 vs 74.2±1.1 %, p<0.01, n=6). A similar improvement was observed in basilar artery (19.9±6.7 vs 48.1±12.3 %, p<0.05, n=6). Aorta from S-DN mice also displayed severely decreased NO donor (sodium nitroprusside, SNP)-induced endothelial-independent relaxation with a right-shifted SNP dose-response, which was also reversed in aorta from tamoxifen-treated S-DN/R+ mice (p<0.01, n=6). To confirm that these effects were specifically due to replacement of RhoBTB1, we assessed vascular function in tamoxifen-treated S-DN mice. Notably, tamoxifen itself did not affect relaxation in response to ACh or SNP, or contraction in response to KCl, endothelin-1 (ET-1) or Prostaglandin F2α in aorta or basilar artery from S-DN (n=4). Interestingly, contraction induced by ET-1, but not KCl, was enhanced in S-DN aorta, and was not improved by restoring RhoBTB1 expression (n=6). This suggests that RhoBTB1 may function specifically by regulating vasodilation pathways. We conclude that RhoBTB1 plays an important role in facilitating vasodilatation in aorta and basilar artery, and loss of RhoBTB1 function explains the vascular dysfunction observed in response to interference with PPARγ in smooth muscle.
Author Disclosures: M. Mukohda: None. S.C. Ibeawuchi: None. C. Hu: None. F.W. Quelle: A. Employment; Significant; University of Iowa. C.D. Sigmund: A. Employment; Significant; University of Iowa. B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH Grants.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2015 by American Heart Association, Inc.