Investigation of the effects of experimental circadian rhythm disorder on the cardiovascular system

Investigation of the Effects of Experimental Circadian Rhythm Disruption on the Cardiovascular System Disruption of circadian rhythm is a critical risk factor that profoundly affects not only sleep patterns but also the fundamental physiological functions of the cardiovascular system. Cardiovascular diseases (CVDs) remain among the leading causes of premature mortality worldwide, and the role of circadian rhythm in the pathogenesis of these diseases is increasingly gaining attention. Pharmacological approaches targeting circadian biology offer innovative therapeutic strategies for the prevention and treatment of cardiovascular diseases. In this study, we aimed to evaluate the multifaceted effects of circadian rhythm disruption on the cardiovascular system and to comparatively investigate the therapeutic potentials of melatonin and nobiletin in this context. A total of 40 male Sprague Dawley rats weighing between 320–370 g were randomly assigned into five groups: Control (K, n=8), Circadian Rhythm Disruption (CRD, n=8), Melatonin (MLT, n=8), Nobiletin 15 mg/kg (NOB15, n=8), and Nobiletin 30 mg/kg (NOB30, n=8). All groups were subjected to a 10-day adaptation period under a 12-hour light / 12-hour dark cycle (12:12 LD). Following this period, all groups except the control group underwent a circadian rhythm disruption protocol. During the experimental phase, melatonin (10 mg/kg/day) and nobiletin (15 mg/kg/day and 30 mg/kg/day) were administered intraperitoneally to the respective groups. At the end of the experiment, hemodynamic parameters were measured via right jugular vein catheterization, and heart and aortic tissues were collected for biochemical, morphometric, histopathological, and immunohistochemical analyses. Among the hemodynamic measurement parameters, the maximum dP/dT value was significantly reduced in the NOB15 group compared to the control group (p<0.05). Regarding minimum dP/dT values, there was a significant difference between groups (p<0.05), with the control group showing the lowest mean. Aortic endothelial MDA levels were significantly higher in the control group than in all other groups (p<0.05). Histopathological analysis revealed pronounced degenerative changes in the CRD group, including myocardial edema, vacuolization, intracellular disintegration, and congestion. These structural impairments were significantly ameliorated by melatonin and nobiletin treatments (p<0.001). Immunohistochemical evaluations showed a significant decrease in PER2 expression and a significant increase in TLR4 expression in the heart and aortic endothelial tissues of the CRD group. Conversely, melatonin and nobiletin treatments markedly and significantly upregulated PER2 expression and downregulated TLR4 expression (p<0.001). The higher dose of nobiletin demonstrated a more pronounced therapeutic effect. In conclusion, our study demonstrates that circadian rhythm disruption induces multifactorial detrimental effects on cardiovascular structure and function. Melatonin and, particularly, nobiletin exhibit protective and regulatory effects at both molecular and functional levels in this pathological context. Keywords: Circadian Rhythm, Cardiovascular, Melatonin, Nobiletin