Short Communication: Ischemia/Reperfusion Tolerance Is Time-of-Day–Dependent

Abstract

Rationale: Cardiovascular physiology and pathophysiology vary dramatically over the course of the day. For example, myocardial infarction onset occurs with greater incidence during the early morning hours in humans. However, whether myocardial infarction tolerance exhibits a time-of-day dependence is unknown. Objective: To investigate whether time of day of an ischemic insult influences clinically relevant outcomes in mice. Methods and Results: Wild-type mice were subjected to ischemia/reperfusion (I/R) (45 minutes of ischemia followed by 1 day or 1 month of reperfusion) at distinct times of the day, using the closed-chest left anterior descending coronary artery occlusion model. Key Words: chronobiology Ⅲ ischemia/reperfusion Ⅲ myocardium N umerous aspects of cardiovascular physiology and pathophysiology demonstrate circadian rhythms. 1 In humans, heart rate, blood pressure, and cardiac output all increase in the early hours of the morning, as does the onset of adverse cardiac events, such as myocardial infarction. 2,3 These rhythms have been attributed primarily to time-of-day oscillations in neurohumoral influences, such as sympathetic or autonomic stimulation. 3,4 Although extracardiac factors undoubtedly play critical roles in modulation of cardiovascular function/dysfunction, increasing evidence suggests that intrinsic factors, such as cellautonomous circadian clocks, likely contribute. 1 Circadian clocks are transcriptionally based molecular mechanisms, composed of positive-and negative-feedback loops, with a free-running period of Ϸ24 hours. 5 This mechanism allows the cell to anticipate alterations in environmental stimuli, through time-of-day-dependent modulation of cellular responsiveness to extrinsic factors. 5 Circadian clocks have been identified/characterized in multiple cardiovascular-relevant cell types, including cardiomyocytes, vascular smooth muscle cells, and endothelial cells. 6 -8 Ubiquitous genetic ablation of circadian clock function markedly influences multiple cardiovascular parameters, including heart rate and blood pressure. 9 We have recently used a CCM (cardiomyocyte-specific circadian clock mutant) mouse to reveal regulation of myocardial gene expression, ␤-adrenergic responsiveness, metabolism, heart rate, and cardiac power by this mechanism. 10,11 Although circadian rhythms in myocardial infarction onset are well established, time-of-day oscillations in myocardial ischemia/reperfusion (I/R) tolerance have not been reported. Given that the cardiomyocyte circadian clock influences Original

Impact of the human circadian system, exercise, and their interaction on cardiovascular function

“…Furthermore, recent animal experimental data indicate increased susceptibility to cardiac ischemia/reperfusion at the sleep-wake transition that is mediated by the cardiomyocyte circadian clock, providing further support for the involvement of the circadian system in the timing of adverse cardiovascular events (35).…”

Circadian clocks: from stem cells to tissue homeostasis and regeneration

“…For instance, CCGs in the murine heart are involved in cardiac glucose and fatty acid metabolism (e.g., Dgat2 , Adpn , Ppp1cc 32), but also electrophysiology which results in oscillatory contractile properties 33 (e.g., Tcap 34 , Kv4.2, and KChIP2 35). Surprisingly, the cardiac‐specific clock not only drives rhythmic output under normal physiological conditions, but also under pathophysiological conditions as noted by its oscillating responsiveness to myocardial infarction mediated by oscillating phosphorylated Akt and GSK‐3 levels 36. In adipose tissue, the clock drives rhythmicity of lipogenesis and lipolysis, and even lipid release 37, via output genes such as Pnpla2 and Lipe 38.…”

Circadian variations of ischemic burden among patients with myocardial infarction undergoing primary percutaneous coronary intervention

“…6 Recently, experimental studies have shown that cardiomyocyte circadian clock affects the response of the heart to various stresses including ischemia/reperfusion by modulating multiple cardioprotective signaling pathways. 6,7 It is well known that onsets of adverse cardiac events, such as sudden cardiac death, 8 stroke, 9 and myocardial infarction increase from 6 AM. 10 The higher incidence of myocardial infarction during the latter part of the morning (6 AM to noon) can be explained by the combination of rise in arterial blood pressure, hormonal stimulation (β-adrenergic, cortisol), 11 hyperreactivity of platelets, 12 and shear stress resulting in atherosclerotic plaque disruption and thrombosis.…”