Vascular PPARγ Controls Circadian Variation in Blood Pressure and Heart Rate through Bmal1

Abstract

SUMMARY Thiazolidinediones (TZDs) are PPARγ activators that exhibit vasculoprotective properties. To determine the vascular function of PPARγ, 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. PPARγ 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 PPARγ target gene. These studies have uncovered a role for vascular PPARγ as a peripheral factor participating in regulation of cardiovascular rhythms.

The daily rhythm of mice

“…Other related nuclear receptors like RORb and PPARc had also an impact on the circadian oscillator or Bmal1 expression [43,47,48]. Nuclear receptors hence target preferentially the stabilizing loop.…”

Peroxisome proliferator-activated receptor α (PPARα) activation advances locomotor activity and feeding daily rhythms in mice

“…6 Activation of PPARa leads to increased levels of BMAL1 protein, which may lead to elevated functions of clock output systems, such as feeding and locomotor activity rhythms. Although PPARg was also found to be a positive regulator of Bmal1, 9 we detected only increased amplitude in the feeding rhythms with no phase advance in the rosiglitazone-treated animals. These results may suggest that PPARa is a stronger regulator of Bmal1 expression than PPARg.…”

“…7 Similarly, the PPARa agonist, rosiglitazone, induced Bmal1 expression. 9 Hence, the interdependence of circadian and metabolic systems jointly regulated by PPARs appears to be extremely important. Herein, our objective was to test the effect of PPARa and PPARg activation using bezafibrate and rosiglitazone, respectively, on metabolism, locomotor activity and feeding circadian rhythms of healthy, non-obese and young mice.…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Ces récepteurs sont pour la plupart soumis à l'horloge puisque leur expression, et par conséquent [34]. Des souris déficientes pour PPARg spécifiquement dans la paroi vasculaire présentent des troubles dans les variations circadiennes de la pression artérielle [43].…”