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Mechanisms and Potential Therapy on Disrupted Blood Pressure Circadian Rhythm in Diabetes

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Mechanisms and Potential Therapy on Disrupted Blood Pressure Circadian Rhythm in Diabetes University of Kentucky UKnowledge Theses and Dissertations--Pharmacology and Nutritional Sciences Pharmacology and Nutritional Sciences 2018 MECHANISMS AND POTENTIAL THERAPY ON DISRUPTED BLOOD PRESSURE CIRCADIAN RHYTHM IN DIABETES Tianfei Hou University of Kentucky, [email protected] Digital Object Identifier: https://doi.org/10.13023/etd.2018.464 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Hou, Tianfei, "MECHANISMS AND POTENTIAL THERAPY ON DISRUPTED BLOOD PRESSURE CIRCADIAN RHYTHM IN DIABETES" (2018). Theses and Dissertations--Pharmacology and Nutritional Sciences. 26. https://uknowledge.uky.edu/pharmacol_etds/26 This Doctoral Dissertation is brought to you for free and open access by the Pharmacology and Nutritional Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacology and Nutritional Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Tianfei Hou, Student Dr. Zhenheng Guo, Major Professor Dr. Howard Glauert, Director of Graduate Studies MECHANISMS AND POTENTIAL THERAPY ON DISRUPTED BLOOD PRESSURE CIRCADIAN RHYTHM IN DIABETES DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Tianfei Hou Lexington, Kentucky Director: Dr. Zhenheng Guo, Associate Professor of Pharmacology and Nutritional Sciences Lexington, Kentucky 2018 Copyright © Tianfei Hou 2018 ABSTRACT OF DISSERTATION MECHANISMS AND POTENTIAL THERAPY ON DISRUPTED BLOOD PRESSURE CIRCADIAN RHYTHM IN DIABETES Arterial blood pressure (BP) undergoes a 24-hour oscillation that peaks in the active day and reaches a nadir at night during sleep in humans. Reduced nocturnal BP fall (also known as non-dipper) is the most common disruption of BP circadian rhythm and is associated with increased risk of untoward cardiovascular events and target organ injury. Up to 75% of diabetic patients are non-dippers. However, the mechanisms underlying diabetes associated non-dipping BP are largely unknown. To address this important question, we generated a novel diabetic db/db-mPer2Luc mouse model (db/db-mPer2Luc) that allows quantitatively measuring of mPER2 protein oscillation by real-time mPer2Luc bioluminescence monitoring in vitro and in vivo. Using this model, we demonstrated that the db/db-mPer2Luc mice have a diminished BP daily rhythm. The phase of the mPER2 daily oscillation is advanced to different extents in explanted peripheral tissues from the db/db-mPer2Luc mice relative to that in the control mice. However, no phase shift is found in the central oscillator, the suprachiasmatic nucleus (SCN). The results indicate that the desynchrony of mPER2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes. Extensive research over the past decades has been focused on how the components of food (what we eat) and the amount of food (how much we eat) affect metabolic diseases. Only recently has it become appreciated that the timing of food intake (when we eat), independent of total caloric and macronutrient quality, is also critical for metabolic health. To investigate the potential effect of the timing of food intake on the BP circadian rhythm, we simultaneously monitored the BP and food intake profiles in the diabetic db/db and control mice using radiotelemetry and BioDAQ systems. We found the loss of BP daily rhythm is associated with disrupted food intake rhythm in the db/db mice. In addition, the normal BP daily rhythm is altered in the healthy mice with abnormal feeding pattern, in which the food is available only during the inactive-phase. To explore whether imposing a normal food intake pattern is able to prevent and restore the disruption of BP circadian rhythm, we conducted active-time restricted feeding (ATRF) in the db/db mice. Strikingly, ATRF completely prevents and restorers the disrupted BP daily rhythm in the db/db mice. While multiple mechanisms likely contribute to the protection of ATRF on the BP daily rhythm, we found that ATRF improves the rhythms of energy metabolism, sleep-wake cycle, BP-regulatory hormones and autonomic nervous system (ANS) in the db/db mice. To further investigate the molecular mechanism by which ATRF regulates BP circadian rhythm, we determined the effect of ATRF on the mRNA expressions of core clock genes and clock target genes in the db/db mice. Of particular interest is that we found among all the genes we examined, the mRNA oscillation of Bmal1, a key core clock gene, is disrupted by diabetes and selectively restored by the ATRF in multiple peripheral tissues in the db/db mice. More importantly, we demonstrated that Bmal1 is partially required for ATRF to protect the BP circadian rhythm. In summary, our findings indicate that the desynchrony of peripheral clocks contributes to the abnormal BP circadian pattern in diabetes. Moreover, our studies suggest ATRF as a novel and effective chronotherapy against the disruption of BP circadian rhythm in diabetes. KEYWORDS: Diabetes, Blood pressure circadian rhythm, Clock genes, Time-restricted feeding, Sympathetic nervous system, db/db mice Tianfei Hou 12-03-2018 MECHANISMS AND POTENTIAL THERAPY ON DISRUPTED BLOOD PRESSURE CIRCADIAN RHYTHM IN DIABETES By Tianfei Hou Dr. Zhenheng Guo Director of Dissertation Dr. Howard Glauert Director of Graduate Studies 12-03-2018 ACKNOWLEDGEMENT First and foremost, I would like to thank Dr. Zhenheng Guo for being my mentor. He gave me the opportunity to work in his fabulous lab and funded me through my Ph.D. study. He guided me to think critically, to do experiments rigorously and to write scientifically. Without his support, this dissertation would not have been possible. I also would like to specifically thank Dr. Ming C. Gong for not only serving on my committee but also giving me tremendous help throughout my Ph.D. training. She was always willing to discuss about and provide suggestions on my project, to share the presentation skills with me and to help with my manuscript writing whenever I needed. A special thanks to my current lab co-worker Dr. Wen Su and my former co- workers Dr. Zhongwen Xie and Mrs. Ming Zhang. Dr. Wen Su helped perform the surgeries on my mice and taught me how to work with the mice. Dr. Zhongwen Xie guided me with the experiments of molecular biology and Mrs. Ming Zhang provided me many of the mice I used in the experiments. Also, I would like to thank other current and former lab co-workers for their kindness and support. It has been a great experience to work with them. I need to thank my other committee members, Drs. Marilyn Duncan and Lisa Cassis who gave me their time and provided their insights on my data. In addition, Dr. Marilyn Duncan also taught me a lot of the circadian field and helped editing my iii manuscript. I also need to thank Dr. David Randall for agreeing to be my outside examiner and help editing my dissertation. Finally, I must thank my parents who supported me to study abroad both financially and emotionally. I am also thankful to all my friends here who made my life outside the lab wonderful. A special thanks to my boyfriend, An Ouyang, who helped me every aspects of my life when I was busy on the Ph. D. study. iv TABLE OF CONTENTS ACKNOWLEDGEMENT ......................................................................................................... iii LIST OF TABLES ..................................................................................................................... x LIST OF FIGURES .................................................................................................................. xi CHAPTER I. INTRODUCTION ................................................................................................ 1 1.1 Diabetes ...........................................................................................................
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