Role of circadian rhythms in heart failure: insights from myocardial energy metabolism

Fig. 1. The circadian clock regulates the rhythm of the cardiac energy metabolism. The circadian clock is composed of a central clock and a peripheral clock. The central clock is located in the suprachiasmatic nucleus (SCN), which regulates the peripheral clock through a neurohumoral mechanism. Illumination resets the SCN to match the ambient shading cycle. The peripheral biological clock of the heart also regulates energy metabolism. When the circadian clock controls the heart, it can flexibly use metabolic substrates to generate energy, and the heart can maintain its normal function. When the circadian clock undergoes physiological or pathological changes, the heart’s energy metabolism will also change accordingly. For example, the normal function of the heart will reduce the metabolism of sugar during sleep, and the decomposition of fat will increase; during exercise and heart failure, the metabolism of sugar will increase, the oxidation of FAs will decrease, and the synthesis of triglycerides in the active heart will increase. Created with Biorender.com

Fig. 2. The circadian clock consists of a transcriptional translation feedback loop. The transcription factors, BMAL1 and CLOCK, form a heterodimer, which binds to the E-box element in the promoter/enhancer region of the target gene and activates its transcription. The target genes include PER, CRY, and REV-ERB. PER and CRY form a heterodimer and interact with BMAL1 and CLOCK to inhibit BMAL1 and CLOCK-mediated transcription, while the nuclear receptor REV-ERB inhibits the transcription of BMAL1 by binding to the RORe of BMAL1. Clock genes initiate many response pathways through different target genes, and play a significant role in various physiological processes according to environmental changes. REV-ERB, Reverse Erb. BMAL1, brain and muscle arnt-like protein-1. CLOCK, circadian locomotor output cycle kaput. PER, period. CRY, cryptochrome. RORE, regulatory element of retinoid X receptor. REVRE, reversed retinoic acid response element. Created with Biorender.com

Fig. 3. Influence of the circadian clock on glucose metabolism. (a) Light upregulates the expression of PER2, resulting in increased activity of phosphofructokinase in glycolysis. The combination of adenosine receptor A2B and PER2 can enhance the glycolytic activity of the ischemic heart and protect the heart. (b) Knockout of BMAL1 upregulates AKT and downstream AS160, promoting glucose transport and uptake. BMAL1 knockout can also downregulate protein phosphatase inhibitor 1, and Gsk-3β upregulation decreases glycogen synthesis. (c) After knocking out REV-ERB, the insulin signaling pathway is activated, promoting glucose uptake and absorption and inhibiting glycogen synthesis. The direction of the arrow represents the up- and downregulation of the molecule. The yellow box represents gene knockout, the light cyan box represents upregulated expression, and the light purple yellow box represents downregulated expression. Created with Biorender.com

Fig. 4. Influence of the circadian clock on fatty acids metabolism. Knockout of REV-ERB in myocardial cells abrogates the inhibitory effects of REV-ERB on BMAL1::CLOCK complexes and E4bp4 and inhibits the expression of fatty acids metabolism-associated genes, resulting in an imbalance in myocardial energy metabolism. The yellow box represents gene knockout, the light cyan box represents upregulated expression, and the light purple box represents downregulated expression. Created with Biorender.com

Fig. 5. Mechanism of heart failure induced by circadian rhythm disorder. The initiation of heart failure occurs at the level of the myocardium and circadian rhythm disorder induces heart failure through multiple pathways. (a) Pathology within the myocardium can include cardiomyocyte death and local remodeling of the extracellular matrix, leading to the progressive formation of a stiff fibrotic tissue mediated by profibrotic signals. (b) At the level of the circadian rhythm regulation loop, important mechanisms include: (1) PER2 enhances glycolysis by activating PFK. (2) After reducing the expression of REV-ERB, the insulin signaling pathway is activated, promoting glucose uptake and absorption and inhibiting glycogen synthesis. (3) The disorder of clock and BMAL1 leads to the reduction of GLUT4 transport, which affects glucose uptake and aggravates insulin resistance. (c) Circadian rhythm disorder affects circadian rhythm regulation loop and causes heart failure. (d) For heart disease caused by circadian rhythm disorder, we can take time therapy: (1) Restore the normal circadian rhythm of patients by improving sleeping environment, standardizing work and rest, etc. (2) Optimize drug…