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Abstract: SA-PO779

The Circadian Clock Protein PER1 Mediates Sex-Dependent Effects on Arterial Stiffness

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Sharma, Ravindra K., University of Florida, Gainesville, Florida, United States
  • Gomes, Joshua, University of Florida, Gainesville, Florida, United States
  • Crislip, G. Ryan, University of Florida, Gainesville, Florida, United States
  • Costello, Hannah Mhairi, University of Florida, Gainesville, Florida, United States
  • Douma, Lauren G., University of Florida, Gainesville, Florida, United States
  • Krishnan, Suraj, University of Florida, Gainesville, Florida, United States
  • Cheng, Kityan, University of Florida, Gainesville, Florida, United States
  • Mohandas, Rajesh, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Gumz, Michelle L., University of Florida, Gainesville, Florida, United States
Background

Increased arterial stiffness is independently associated with adverse cardiovascular events and improvement in pulse wave velocity (PWV), a noninvasive clinical index of arterial stiffness, corelates with better survival. The Circadian Protein Period 1 (PER1) is important to the maintenance of circadian rhythms and regulates a wide array of physiological functions including blood pressure. Lysyl Oxidase (LOX), an extracellular cuproenzyme that mediates collagen crosslinking, is integral to maintain vascular stiffness, and exhibits a circadian pattern of expression. Thus, we hypothesize that disrupted circadian clock function and upregulation of LOX could be a key mechanism for increased vascular stiffness.

Methods

Male and female C57BL/6J (15-16 weeks old) global PER1 Knock-out (KO) and WT mice (n=6) subjected to echocardiographic measurement of PWV to evaluate aortic stiffness. Further, cell specific mRNA expression of LOX was assessed in aortic tissue using situ hybridization (ISH). Aortic segments were mounted in ex-vivo wire myograph to analyze changes in vascular reactivity and functions. Finally, morphometric measurements were used to assess structural changes and remodeling in H&E stained aortic sections. Comparisons between groups were made using t-test and p-value <0.05 was accepted as significant.

Results

Knockout of PER1 resulted in an increased PWV in male (Con:179±32, PER1 KO: 306±47 cm/s, p<0.001) but not in female mice (Con:219±14, PER1 KO: 225 ± 23 cm/s, p<0.80) compared to age matched WT controls. This was associated with an increased LOX mRNA expression (~2.7 fold; p<0.01) in the aorta of PER1 KO compared to WT mice. Morphometric analysis showed an increased adventitia thickness (30%; p<0.05) in aortas of PER1KO mice. However, vascular functions/reactivity in PER1 KO mice aorta were slightly increased but this did not reach statistical significance.

Conclusion

Our findings suggest that disruption of circadian rhythm by deleting PER1 increases arterial stiffness in male but not in female mice. Increased LOX mediated changes in extracellular matrix are at least in part responsible for the pathogenesis of arterial stiffness in these mice. Inhibition of excessive LOX may have therapeutic potential in alleviating pathogenic increased vascular stiffness.

Funding

  • Other NIH Support