The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function

Abstract

It is becoming increasingly clear that the intrinsic properties of both the heart and vasculature exhibit dramatic oscillations over the course of the day. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e., neurohumoral factors) and intracellular (i.e., circadian clock) influences. The intracellular circadian clock is composed of a series of transcriptional modulators that together allow the cell to perceive the time of day, thereby enabling preparation for an anticipated stimulus. These molecular timepieces have been characterized recently within both vascular smooth muscle cells and cardiomyocytes, giving rise to a multitude of hypotheses relating to the potential role(s) of the circadian clock as a modulator of physiological and pathophysiological cardiovascular events. For example, evidence strongly supports the hypothesis that the circadian clock within the heart modulates myocardial metabolism, which in turn facilitates anticipation of diurnal variations in workload, substrate availability, and/or the energy supply-to-demand ratio. The purpose of this review is therefore to summarize our current understanding of the molecular events governing diurnal variations in the intrinsic properties of the heart, with special emphasis on the intramyocardial circadian clock. Whether impairment of this molecular mechanism contributes toward cardiovascular disease associated with hypertension, diabetes mellitus, shift work, sleep apnea, and/or obesity will be discussed.

Diurnal profiling of neuroendocrine genes in murine heart, and shift in proopiomelanocortin gene expression with pressure-overload cardiac hypertrophy

“…For experiments examining gene rhythmicity in vitro, confluent cells were first starved in serum-free media (supplemented with 5% pen-strep) for 12 h. The cells were then serum shocked with 20% FBS for 30 min. Serum shock is currently the standard method used to synchronize cells in culture (Hurst et al 2002, Young 2006. Following serum shock, the cells were returned to normal culture conditions and samples were collected every 4 h for 36 h. Expression was determined by RT-PCR, as opposed to microarray.…”

The circadian protein Clock localizes to the sarcomeric Z-disk and is a sensor of myofilament cross-bridge activity in cardiac myocytes

“…In rats that are nocturnal, contractile performance, carbohydrate oxidation, oxygen consumption and the expression of metabolic genes are greatest at night [3]. The myocardium expresses a number of circadian genes including BMAL1(brain and muscle ARNT-like protein1), Clock, cryptochrome (CRY) and the period genes (PER1, PER2, PER3) which are thought to regulate a number of cellular processes [4]. Clock protein exerts its effects by forming a heterodimer with BMAL1 which increases the transcription of target genes including PER and CRY genes.…”

A sincronização noradrenérgica e o papel da insulina na modulação da síntese da melatonina pela glândula pineal de ratos.

“…Circadian rhythms in myocardial physiology and pathophysiology have classically been explained in terms of extracardiac influences (23,28,31,37). Changes in autonomic, sympathetic, and adrenergic stimulation, nutrients (e.g., glucose, fatty acids, lipoproteins), circulating hormones (e.g., insulin, cortisol, adipokines), as well as vascular resistance and afterload, have all been suggested to influence circadian rhythms in myocardial gene expression, metabolism, and contractile function (42). The present study highlights the existence of an intrinsic molecular mechanism within the cardiomyocyte that likely augments or modulates myocardial biology.…”

“…Due to known close relationships between myocardial contractile function and metabolism (34), as well as the suggestion that peripheral circadian clocks likely influence cellular metabolism (41,42), myocardial metabolic fluxes were measured in wild-type and CCM hearts ex vivo, at both normal and high workloads. When perfused at a normal workload, neither rates of exogenous oleate oxidation, exogenous glucose oxidation, nor lactate release rates (net, 14 C-labeled, endogenously derived) exhibited a time-of-day dependence in wild-type hearts under normal workload conditions (Fig.…”

“…Almost every mammalian cell possesses an intrinsic circadian clock, a transcriptionally based molecular mechanism capable of regulating multiple cellular functions. In terms of the cardiovascular system, circadian clocks have been characterized within multiple cell types, including cardiomyocytes (7,42); however, little is known regarding the influence of intramyocellular circadian clocks on cardiovascular physiology and pathophysiology. This is particularly relevant, given the possibility that impairment of the circadian clock within the cardiomyocyte may significantly alter cardiac function, pathogenesis of cardiovascular disease (CVD), and/or treatment strategies during CVD states (e.g., chronopharmacology) (42).…”