Circadian Rhythms

Virtually, all mammals, including humans have a circadian mechanism that controls the timing of many key physiological processes in response to a variety of environmental cues. The regulation of the molecular machinery of circadian rhythms sustains of 24 hours cycles and can differ between cell types and organisms in accordance with different metabolic requirements. The regulation of the circadian machinery begins with input from light/dark signals that are absorbed by photoreceptors in our eyes, followed by transmission through the hypothalamic master pacemaker to the rest of the body, via a combination of neural and humoral signals. Although the circadian clock mechanism outputs govern many biochemical processes as a function of the time of the day or night, the mechanism can also operate in the absence of light/dark cycles. In this case, the endogenous clocks are dynamically regulated and can be modified by other external cues, such as nutrition, temperature or environment. These signals modulate circadian regulation to promote physiological adaptations to tissue-specific metabolic needs. Disruption of the normal circadian rhythm can lead to various pathologies, including diabetes, cardiovascular disease, as well as, cardiometabolic syndrome (CMS).

Cardiometabolic syndrome 

Cardiometabolic syndrome (CMS) is characterized by insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central adiposity. Individuals with CMS are two times more likely to die from coronary heart disease and three times more likely to have a heart attack or stroke than those who do not have the syndrome. Moreover, CMS is characterized by changes in cardiac structure and function which increase the risk for future development of heart failure (HF) among obese individuals. Notably, cardiometabolic HF is more common in women, and with higher prevalence for HF with preserved ejection fraction (HFpEF) subtype. Cardiometabolic HF is characterized by myocardial lipid accumulation, lipotoxic damage, and increased myocardial triglyceride content.

Our Research Program

Disrupted circadian rhythm, such as seen in shift workers, has become extremely common in developing countries, accounting for 30% of the working force. Studies are showing that individuals who work shifts have an increased risk of developing cardiac disease. Notably, individuals who work shifts tend to increase their food intake, preferably carbohydrate-rich foods, which leads to abnormalities in lipid and triglycerides levels, increase in glucose levels and high blood pressure. Many population studies support these observations by showing that circadian disruption, such as seen in shift work, is closely associated with increased risk for CMS due to circadian misalignments caused by chronically irregular sleeping and eating times. 

Our research program focuses on discovering novel key genes and networks that are associated with both circadian rhythms and metabolic function in females, toward developing innovative therapeutic strategies to treat cardiometabolic dysfunction. Therefore, we focus on understanding how disruption to circadian machinery provokes cardiometabolic dysfunction that leads to the development of HF in response to CMS in females. Another important aspect of our research program is to explore nutritional stimulators that can mitigate the development of cardiometabolic HF in a circadian-dependent manner. 

Rabinovich-Nikitin I, and Kirshenbaum LA. Rev-erb-mediated Regulation of Cardiac Metabolism in the Obesity Paradox. Circulation. 145(6):465-468. 2022.

Rabinovich-Nikitin I, Love M, Kirshenbaum LA. Intersection of Circadian Rhythms and Mitochondrial Quality Control Regulation in the Heart. Biochim Biophys Acta Mol Basis Dis. 1868(4):166354. 2022.

Zacharioudakis E, Agianian B, Kumar V, Biris N, Garner T, Rabinovich-Nikitin I, Ouchida AT, Margulets V, Nordstrom L, Riley J, Dolgalev I, Chen Y, Wittig A, Pekson R, Tsirigos A, Kirshenbaum LA, Kitsis R, Gavathiotis E. Modulating mitofusins to control mitochondrial function and signaling. Nat Commun. 13(1):3775. 2022. 

Rabinovich-Nikitin I*, Blant A*, Dhingra R, Kirshenbaum LA and Czubryt MP. NF-κB p65 Attenuates Cardiomyocyte PGC-1α Expression in Hypoxia. Cells. 11(14), 2193. 2022.

Rabinovich-Nikitin I, Rasouli M, Reitz CJ, Posen I, Margulets V, Dhingra R, Khatua TN, Thliveris J, Martino TA, and Kirshenbaum LA. Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress. Autophagy. 17(11):3794-3812. 2021.

Rabinovich-Nikitin I, Kirshenbaum LA. GSK-3β Mediates Cardiac Senescence through Inhibition of Ulk1 Directed Autophagy. J Cardiovasc Aging. 1:14. 2021.

Aziz I, McMahon A, Friedman D, Rabinovich-Nikitin I, Kirshenbaum LA, Martino TA. Circadian Influence on Inflammatory Response during Cardiovascular Disease. Curr Opin Pharmacol. 57:60-70. 2021.

Rabinovich-Nikitin I, Lieberman B, Martino TA and Kirshenbaum, LA. Circadian Regulated Cell Death in Cardiovascular Diseases. Circulation. 139(7):965-980; 2019. 

Rabinovich-Nikitin I, Dhingra R, and Kirshenbaum LA. Activation of Mitophagy in High Fat Diet-Induced Diabetic Cardiomyopathy. Circ Res. 24(9):1288-1290; 2019.

Rabinovich-Nikitin I and Kirshenbaum LA. Exercise-Induced Myonectin Protects Against Ischemia-Reperfusion Injury. Circ Res. 123(12):1264-1266; 2018.

2023    Winner, Buddha Dawn Early Career Award, International Academy of Cardiovascular Sciences (IACS), North American Session

2023    Outstanding Early Career Investigator Award, NIH Progenitor Cell Translational Consortium

2022    Winner, Louis N. and Arnold M. Katz Basic Science Research Prize for Early Career Investigators, American Heart Association (AHA)

2022, ISHR International Best Presentation Award, International Society for Heart Research (ISHR), International Council

2022, ISHR ECI Travel Award, International Society for Heart Research (ISHR), International Council

2021, Winner, Dr. Roberto Bolli Young Investigator Competition Award, International Academy of Cardiovascular Sciences (IACS)

2020, Martha Donovan Women’s Leadership Development Award, Winnipeg Foundation, University of Manitoba

2020, ISHR NAS2020 Young Investigator Competition Award Finalist, International Society for Heart Research North American Section (ISHR NAS)

2020, Paul Dudley White International Scholar, Hypertension Scientific Sessions, American Heart Association (AHA)

2020, New Investigator Travel Award, Hypertension Scientific Sessions, American Heart Association (AHA)

2019, Sr. Jacqueline St-Yves Publication Award for Best Paper, Institute of Cardiovascular Sciences, Canada

2018, Paul Dudley White International Scholar, Basic Cardiovascular Sciences Scientific Sessions, American Heart Association (AHA)

2018, New Investigator Travel Award, Basic Cardiovascular Sciences Scientific Sessions, American Heart Association (AHA)

2017, Arnold Naimark Young Investigator Award, Institute of Cardiovascular Sciences, Canada

2017- 2021, Canadian Institute of Health Research (CIHR), Postdoctoral Fellowship Award

2017, International Cell Death Society (ICDS) – Cell Death in Development and Disease Conference Travel Award, Israel 

• St. Boniface Hospital Foundation
• Canadian Space Agency (CSA)                                                                                       
• American Academy of Sleep Medicine (AASM) Foundation                                        
• Manitoba Medical Service Foundation (MMSF)
• The Winnipeg Foundations