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Abstract: PO2127

The Circadian Clock Provides Beneficial Effects Against the Endothelial Dysfunction to Promote Atherogenesis by Regulating Heme Oxygenase 1 Expression

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Author

  • Negoro, Hideyuki, Harvard Medical School, Boston, United States
Background

The circadian clock is a molecular mechanism that confers 24 hour variations in gene expression and function to regulate number of physiological functions in humans. Disruption of the clock is associated with pathological remodeling in the arterial structure and vascular stiffness. Chronic circadian clock disruption is also associated with dysfunction in endothelial signaling and responses.
Heme oxygenase-1 (HO-1) is an intracellular enzyme which catalyzes the oxidation of heme to generate ferrous iron, carbon monoxide, and biliverdin, which is subsequently converted to bilirubin. These products have anti-inflammatory, anti-apoptotic and anti-thrombotic properties. In this study, we observed if the deletion of Bmal1, a critical component of the circadian clock, can influence HO-1 which play an important part in the protection of vascular diseases.

Methods

Congenic 12- to 16-week-old male, wild-type and Bmal1-KO littermate mice were generated from heterozygote breedings to be used for these studies. We also knocked down Bmal1 to evaluate the protein levels of HO-1 expression in the knocked down cells.

Results

Endothelial function was reduced in aorta from Bmal1-KO mice. In aorta from Bmal1 KO mice, there was a reduction in HO-1 expression in mice with a dysfunctional circadian rhythm. Moreover, Bmal1 KO mice display pre-mature aging to have a dramatic prothrombotic phenotype. This phenotype is linked to changes in the regulation of key risk factors for cardiovascular disease. These include HO-1 which is significantly reduced in Bmal1 KO mice. We also confirmed that HO-1 levels follow a circadian pattern and this pattern was absent in Bmal1 KO mice.

Conclusion

These findings indicate that circadian clock provides beneficial effects against the endothelial dysfunction to promote atherogenesis by regulating HO-1 expression. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.

Funding

  • Government Support - Non-U.S.