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. 2008 Dec;8(6):482-91.
doi: 10.1016/j.cmet.2008.10.009.

Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1

Ningning Wang  1 , Guangrui Yang, Zhanjun Jia, Hui Zhang, Toshinori Aoyagi, Sunhapas Soodvilai, J David Symons, Jurgen B Schnermann, Frank J Gonzalez, Sheldon E Litwin, Tianxin Yang
Affiliations

Vascular PPARgamma controls circadian variation in blood pressure and heart rate through Bmal1

Ningning Wang et al. Cell Metab. 2008 Dec.

Abstract

Thiazolidinediones (TZDs) are PPARgamma activators that exhibit vasculoprotective properties. To determine the vascular function of PPARgamma, we analyzed Tie2Cre/flox and SM22Cre/flox mice. Unexpectedly, both knockout strains exhibited a significant reduction of circadian variations in blood pressure and heart rate in parallel with diminished variations in urinary norepinephrine/epinephrine excretion and impaired rhythmicity of the canonical clock genes, including Bmal1. PPARgamma expression in the aorta exhibited a robust rhythmicity with a more than 20-fold change during the light/dark cycle. Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms.

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Figures

Fig. 1
Fig. 1
Validation of PPARγ deletion in the vascular cells. (A) Schematic illustration of primer design for detection of the PPARγ foxed allele (S1 and AS1) and PPARγ mRNA expression (S2 and AS2). (B) PCR analysis of the PPARγ floxed allele in ECs and VSMCs freshly isolated from PPARγf/f (f/f), SM22Cre/flox (SM22), Tie2Cre/flox (Tie2) mice using primers S1 and AS1. Amplification of GAPDH gene served as a loading control. C, RT-PCR analysis of PPARγ mRNA in ECs and VSMCs from the three strains of mice. CD31 and α-SMA are markers of EC and SMC, respectively. α-Tubulin was used as a loading control. Shown are representatives of 2~3 experiments.
Fig. 2
Fig. 2
Altered diurnal rhythms in MAP and HR in SM22Cre/flox and Tie2Cre/flox mice. (A) Hourly recordings of MAP over 24 h. CT0, the beginning of a subjective circadian period (6:00am). (B) The average MAP during light and dark phases. (C) The maximal variations of MAP over 24 h. (D) Hourly recordings of HR over 24 h. (E) The average HR during light and dark phases. (C) The maximal variations of HR over 24 h. N=5–7 in each group. Data are mean ± SE.
Fig. 3
Fig. 3
Altered diurnal rhythms in sympathetic activity in SM22Cre/flox and Tie2Cre/flox mice. (A) 12-h urine output of NE during light and dark phases. (B) Night-to-day ratios of urinary NE. (C) 12-h urine output of Epi. (D) Night-to-day ratios of urinary Epi. N=6–7 in each group. Data are mean ± SE.
Fig. 4
Fig. 4
Real time RT-PCR of analysis of gene expressions in the aortae and livers of PPARγf/f, SM22Cre/flox and Tie2Cre/flox mice at 4-h intervals. X-axis represents circadian time (CT0, the beginning of subjective light cycle). (A) PPARγ expression in PPARγf/f mice; (B–I) Expressions of canonical clock genes in aortae and livers in the three mouse strains. N=5 in each time point. Shown are mean ± SE. *, P<0.05 and #, P<0.01 vs. PPARγf/f.
Fig. 5
Fig. 5
PPARγ regulates Bmal1 gene transcription. PPARγf/f mice were treated with rosiglitazone (RGZ) at 320 mg/kg diet for 2 days. The thoracic aortae were harvested and subjected to real time RT-PCR (A) and ChIP assay (B). For luciferase assay, mouse SVEC4-10 cells (C) and mouse M1 cells (D) transiently transfected with constructs containing wild-type Bmal1 promoter or Bmal1 promoter with mutated PPRE, and cotransfected with expression vectors for PPARγ, RXRα, and β-galactosidase. In (E), the PPRE site is shown in green and mutated sequences are indicated by lower-case letters. Confluent cells were exposed for 24 h with vehicle or 2 µM RGZ. Luciferase activity was normalized by β-galactosidase activity. In (A), (C), and (D), N = 4–5 per group and data are mean ± SE. In (B), the two lanes in each group represent two separate animals.
Fig. 6
Fig. 6
Effects of lightness/darkness and restricted feeding on the cyclic expression of vascular PPARγ. (A) PPARγ mRNA expression in the aortae of PPARγf/f mice kept under regular 12:12 h light/dark cycle (LD), constant lightness (LL), or constant darkness (DD) for 3 days. (B) PPARγ mRNA expression in the aortae of PPARγf/f mice kept under the regular LD cycle and fed only during the light or dark phase. All animals were killed at CT4 and CT16, and aortic PPARγ expression was determined by real time RT-PCR. N=5 in each group. Shown are mean ± SEM. (C) Proposed role of PPARγ in integrating the environmental signals, the clock, the cardiovascular function, and metabolism.
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