Cosinor Analysis Reveals Non‐dipping Hypertension in Mixed Background Strain Mice Lacking the Circadian Clock Protein PER1

Abstract

Cardiovascular disease is the leading cause of death among Americans. Hypertension is the leading risk factor for cardiovascular disease, thus blood pressure (BP) regulation is imperative for maintaining cardiovascular health. BP exhibits a circadian rhythm that is regulated through many mechanisms. Humans experience a BP rhythm resulting in a 10–20% dip in BP during their resting period. Individuals who fail to maintain this dip, termed non‐dippers, are associated with worse cardiovascular outcomes. The circadian clock mechanism, which includes the transcription factors PERIOD, BMAL1, CLOCK, and CRYPTOCHROME, is necessary to maintain this rhythm. Past studies in our lab have shown that global loss of PER1 leads to non‐dipping hypertension in male C57BL/6 mice in response to high salt diet plus an aldosterone analogue desoxycorticosterone pivalate‐salt (DOCP) (Solocinski et al. 2017). The goal of this study was to determine the BP phenotype of Per1 knockout (KO) mice on a salt‐sensitive 129/sv/s1s4 background strain. 129/sv/s1s4 mice were implanted with radiotelemetry devices and maintained in a normal 12‐hour light/dark period. BP was monitored continuously while the mice were subjected to a control diet, a high salt (HS) diet, or a HS diet plus treatment with an aldosterone analogue DOCP. BP rhythms were analyzed through the program Cosinor (www.circadian.org) to determine the mesor, amplitude, and acrophase. When evaluating a cosine wave, the mesor is the midline between the peak and the trough, the amplitude is the measure of the mesor to the peak, and the acrophase is the time point of the peak. These values were then used to discern whether the mice maintained a BP rhythm. The 129/sv/s1s4 Per1 KO experienced a 9‐mmHg increase in BP in response to HS/DOCP (P<0.01, n=8). In contrast, the wild type (WT) mice (n=5) did not experience a significant increase in BP after HS/DOCP. Furthermore, the KO mice had a 2.4‐mmHg decrease in amplitude (P=0.01), whereas the WT mice did not exhibit a significant decrease in amplitude. The WT mice on control diet exhibited a 12.8% dip in BP during their inactive period compared to their active period, which insignificantly decreased to an 11.5% dip on HS/DOCP diet. However, the KO mice on control diet had an 11% dip, which decreased to 5.4% dip on HS/DOCP diet (P<0.05, n=5–8). These data demonstrate that loss of Per1 in male 129/sv/s1s4 mice leads to a non‐dipping phenotype in response to HS/DOCP treatment. Importantly, these findings represent the reproducibility of the non‐dipping hypertension phenotype we previously observed in C57BL/6 mice in a distinct strain on a mixed background.Support or Funding InformationAmerican Physiological Society Undergraduate Summer Fellowship Program; American Society of Nephrology Foundation for Kidney ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.