Sex-specific Role For The Circadian Clock Protein PER1 In Aortic Stiffness

Background: Increased aortic stiffness is independently associated with an increased risk of cardiovascular events and improvement in aortic stiffness positively correlates with better survival. Period 1 (PER1) is a core circadian clock protein and previous studies have shown that global or kidney-specific knockout (KO) of PER1 results in salt-sensitive hypertension, but the role of PER1 in the vasculature remains unknown. The goal of the present study was to test the hypothesis that loss of PER1 would lead to increased aortic stiffness. Methods: Male and female C57BL/6J (16-18 weeks old) mice with global or vascular smooth muscle cell (VSMC)-specific PER1 KO (n=7-10) and control mice (WT) were subjected to echocardiographic measurement of pulse wave velocity (PWV) to evaluate aortic stiffness. We further investigated if treatment with high salt diet plus an aldosterone analog (HS-DOCP, deoxycorticosterone pivalate) has any additional effect on aortic stiffness in male VSMCs-specific PER1 KO mice. Results: In mice on a normal diet, global KO of PER1 resulted in increased PWV in males (WT: 202±8, PER1 KO: 287±27 cm/s, p<0.01) but not in female mice (WT:219±14, PER1 KO: 225 ± 23 cm/s, p<0.80) compared to age-matched wild type. Further, morphometric analysis of the aorta showed increased adventitia thickness in male global PER1 KO mice (WT: 41.7±2.3, PER1 KO: 54.6±2.4 um, (p<0.01). These data led us to generate VSMC PER1 KO mice by crossing Tagln Cre mice with floxed PER1 mice. VSMC KO was confirmed by recombination PCR. PWV was not different between male VSMC PER1 KO and Cre negative littermate control (CNTL) mice on normal diet, however, it was increased in VSMC PER1 KO mice after treatment with HS-DOCP (CNTL: HS-DOCP: 241 ±12, PER1 KO: HS-DOCP: 307±18 cm/s, p<0.01). PWV in female VSMCs PER1 KO mice was not statistically significant compared to littermate CNTL mice (CNTL: 247±12, VSMC PER1 KO: 233 ± 25 cm/s, p<0.50). Conclusion: Our findings indicate that loss of the clock protein PER1 increases aortic stiffness in male but not in female mice suggesting a sex specific role for the circadian clock in the pathology of aortic stiffness. Further studies are warranted to identify the potential mechanisms involved in the pathogenesis of PER1-dependent aortic stiffness.