The intrinsic circadian clock within the cardiomyocyte

Abstract

Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully functional clock mechanism. The present study exposes oscillations of circadian clock genes [brain and arylhydrocarbon receptor nuclear translocator-like protein 1 (bmal1), reverse strand of the c-erba␣ gene (rev-erba␣), period 2 (per2), albumin D-element binding protein (dbp)] for isolated adult rat cardiomyocytes in culture. Acute (2 h) and/or chronic (continuous) treatment of cardiomyocytes with FCS (50% and 2.5%, respectively) results in rhythmic expression of circadian clock genes with periodicities of 20 -24 h. In contrast, cardiomyocytes cultured in the absence of serum exhibit dramatically dampened oscillations in bmal1 and dbp only. Zeitgebers (timekeepers) are factors that influence the timing of the circadian clock. Glucose, which has been previously shown to reactivate circadian clock gene oscillations in fibroblasts, has no effect on the expression of circadian clock genes in adult rat cardiomyocytes, either in the absence or presence of serum. Exposure of adult rat cardiomyocytes to the sympathetic neurotransmitter norephinephrine (10 M) for 2 h reinitiates rhythmic expression of circadian clock genes in a serumindependent manner. Oscillations in circadian clock genes were associated with 24-h oscillations in the metabolic genes pyruvate dehydrogenase kinase 4 (pdk4) and uncoupling protein 3 (ucp3). In conclusion, these data suggest that the circadian clock operates within the myocytes of the heart and that this molecular mechanism persists under standard cell culture conditions (i.e., 2.5% serum). Furthermore, our data suggest that norepinephrine, unlike glucose, influences the timing of the circadian clock within the heart and that the circadian clock may be a novel mechanism regulating myocardial metabolism.heart; metabolism; neurohumoral; rat; zeitgebers CIRCADIAN CLOCKS are controlled by a set of genes that generate self-sustained positive and negative transcriptional feedback loops with a free-running period of 24 h (7,11,40). This molecular mechanism is intrinsic to the cell, persisting in cultured cells such as fibroblasts, vascular smooth muscle cells, and various cell lines (3,13,20,23). Circadian clocks confer the selective advantage of anticipation, conditioning the cell to changes in its environment, such that it can respond rapidly to a specific extracellular signal at an appropriate time of the day. For example, our laboratory (30) has recently hypothesized that the circadian clock within cardiac and skeletal muscle allows the myocytes to anticipate diurnal variations in circulating fatty acids through modulation of fatty acid oxidative capacity at a transcriptional level. However, the existence of an intracellular circadian clock mechanism that is intrinsic to either the cardiomyocyte or...

The Circadian Clock within the Cardiomyocyte Is Essential for Responsiveness of the Heart to Fatty Acids

“…bmal1 and rev-erba␣). These oscillations exhibit a periodicity of between 20 and 24 h, with temporal patterns similar to those observed in the intact heart in vivo, consistent with the operation of a circadian clock within the cardiomyocyte (19).…”

“…This molecular mechanism confers the selective advantage of anticipation, permitting the cell to respond rapidly to a given stimulus at the appropriate time of the day (24). Circadian clocks have been identified in a vast array of mammalian cell types, including components of the cardiovascular system (19,20,25,26).…”

“…Recently we characterized the circadian clock within the cardiomyocytes of the rat heart (19). Isolated adult rat cardiomyocytes (ARCs), 3 when cultured in the presence of serum, exhibit oscillations in mRNAs encoding for known circadian clock components (e.g.…”

A critical role of sympathetic nerve regulation for the treatment of impaired daily rhythm in hypertensive Dahl rats

“…Although the causal relationship between b-blockers and the clock system has not yet been clinically elucidated, it has been reported that norepinephrine influences the timing of the circadian clock within cardiomyocytes. 20 This means that the regulation of sympathetic neurotransmitters using b-blockers affects the clock system in cardiovascular cells. The b-blocker treatment affects not only physiological conditions but also transcriptional conditions, such as peripheral clock genes.…”

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

“…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).…”