Abstract: SA-PO335
The Circadian Clock Provides Beneficial Effects Against the Endothelial Dysfunction to Promote Atherogenesis by Regulating Angiotensin II Generation and Vascular Endothelial Growth Factor Expression
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Author
- Negoro, Hideyuki, Harvard Medical School, The Graduate School of Project Design, Tokyo, Japan
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. In this study, we observed if the deletion of Bmal1, a critical component of the circadian clock, can influence growth factors, such as Angiotensin II or Vascular Endothelial Growth Factor (VEGF) which play an important part in the progression 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 Angiotensin II and VEGF 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 an increase in Angiotensin II and VEGF 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 Angiotensin II and VEGF, which are significantly elevated in Bmal1 KO mice. We also confirmed that PDGF 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 Angiotensin II and VEGF expression. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.
Funding
- Government Support - Non-U.S.