2017 Cardiovascular Research Day Abstract Book

41
Desynchrony of Tissue Oscillators and Compromised Blood Pressure Circadian Rhythm in a
Novel Diabetic Db/Db-Mper2luc Mouse Model
Tianfei Hou, MS 1 • Wen Su, MD 1 • Ming Gong, MD, PhD 2 • Zhenheng Guo, PhD 1
1Department of Pharmacology and Nutritional Sciences, University of Kentucky • 2 Department of
Physiology, University of Kentucky
Graduate Student
Diabetic patients have a high prevalence of blood pressure (BP) circadian rhythm disruption mostly
manifested as reduced BP dipping during the inactive phase (non-dipping profile). Accumulating
evidence demonstrates a pathophysiological link between end-organ damage and non-dipping BP.
Clock gene dysregulation may link diabetes with non-dipping BP but comprehensive study of clock
gene oscillation dysregulation in diabetes has been hampered by the impractical requirement of
intensive timed sampling. To address this issue, we generated a novel diabetic model, db/dbmPer2Luc
mouse, by crossing the extensively used type 2 diabetic db/db mice with the clock gene
Period 2 (mPer2) luciferase knock-in mPer2Luc mice. The db/db-mPer2Luc mice were obese,
diabetic and had non-dipping BP. Real-time measurement of bioluminescence of the many tissues
explanted from the db/db-mPer2Luc mice revealed that the phases of the mPer2 circadian
oscillations shifted to different extents in aorta, mesenteric artery, kidney, liver, white adipose
tissue and thymus, but no phase shift was detected in the central SCN tissue, or the adrenal gland
and lung. The desynchrony of the tissue oscillators in the db/db-mPer2Luc mice was associated
with compromised circadian rhythms in respiratory exchange ratio. Moreover, the time-of-day
variations in vascular contractile responses and in baroreflex sensitivity were abolished. Taken
together, we generated a novel diabetic db/db-mPer2Luc mouse model. Using this model, we
revealed a desynchrony among tissue oscillators, a loss of the time-of-day variations in vascular
contractile responses and baroreflex sensitivities, all of which likely contribute to the dampening of
BP circadian rhythm in diabetes.
57