Role of CK1ε-regulated PERIOD2 in STZ-induced diabetic myocardial injury.

Bo Zhao,Meng Jiang,Qin Huang,Shaoqing Lei,Zhen Qiu,Zhong-Yuan Xia

doi:10.31083/j.fbl2702058

Abstract

Circadian rhythms are fundamental to regulating metabolic processes and cardiovascular functions. Phosphorylated PERIOD2 (PER2) is a key factor in determining the period of the mammalian circadian clock. Moreover, casein kinase 1ε (CK1ε) primes the PER2 phosphoswitch and its stability. While diabetes contributes to the disorder of the circadian system, changes in PER2 forms and their regulatory mechanisms during diabetes remain unclear. In this study, we examined the impact of diabetes on PER2 and CK1ε signaling in the heart to determine the potential mechanism between them. A Type-1 diabetic rat model was established by intraperitoneally injecting rats with streptozotocin. General characteristics, cardiac function, histology, serum biochemistry, apoptosis index and circadian rhythm were analyzed in controls and diabetic rats treated with or without PF-670462 (a CK1ε inhibitor). A high-glucose model was created with H9c2 cells and treated with PF-670462 and PER2 siRNA. Cell viability, LDH release, dead/live rate and histology were determined to assess cellular injuries. RT-PCR and Western blot were used to evaluate the expression of PER2, CK1ε, phosphorylated PER2, and immunofluorescence (IF) was employed to determine PER2's location. STZ-induced diabetes prolonged PER's period and upregulated the expression of CK1ε and phosphorylated PER2 compared to the controls. Inhibiting CK1ε and PER2 with PF-670462 downregulated the phosphorylation at Ser662 and the nuclear entry of PER2 in high glucose conditions. In addition, pharmacologically or genetically suppressing PER2 mitigated high-glucose-instigated myocardial injury. Diabetes compromised PER2 in association with activated CK1ε signaling. Targeting CK1ε-regulated PER2 alleviates myocardial injuries in the presence of high glucose.

Highlights

Diabetes mellitus (DM) is a lifelong metabolic disease and its prevalence continues to increase [1,2]
Rats in the non-diabetic group were injected with the same amount of citrate buffer. 72 hours after STZ administration, blood was drawn from the tail vein of each rat once to measure fasting blood glucose (FBG)
General characteristics, including body weight, heart weight, water intake, food intake, and FBG, were significantly altered in STZ-induced diabetic rats compared to their control counterparts (Fig. 1B)

Summary

Introduction

Diabetes mellitus (DM) is a lifelong metabolic disease and its prevalence continues to increase [1,2]. DM affects myocardial morphology, metabolism, gene expression, physiological function, and much more. Circadian rhythms are fundamental to regulating metabolic processes and cardiovascular functions. We examined the impact of diabetes on PER2 and CK1ε signaling in the heart to determine the potential mechanism between them. Cardiac function, histology, serum biochemistry, apoptosis index and circadian rhythm were analyzed in controls and diabetic rats treated with or without PF-670462 (a CK1ε inhibitor). RT-PCR and Western blot were used to evaluate the expression of PER2, CK1ε, phosphorylated PER2, and immunofluorescence (IF) was employed to determine PER2’s location. Results: STZ-induced diabetes prolonged PER’s period and upregulated the expression of CK1ε and phosphorylated PER2 compared to the controls. Targeting CK1ε-regulated PER2 alleviates myocardial injuries in the presence of high glucose

Methods

Results

Discussion

Conclusion