c-Myc: an emerging participant in heart failure

Figures

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  Figure 1. The c-MYC protein (A) the c-MYC protein structure with all the main domains annotated; (B) the stabilization and degradation mechanism of c-Myc protein. bHL-H-LZ, basic Helix-Loop-Helix Leucine Zipper Domain; FBXW7, F-Box and WD repeat domain-containing 7; MAX, Myc-associated protein X; MB, Myc boxe; NLS, nuclear localization signal; PEST, proline, glutamic acid, serine, and threonine - rich domain; Ser, S erine; TAD, transactivation domain; Thr, threonine.

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  Figure 2. Role of c-Myc in cardiac hypertrophy and fibrosis in heart failure in heart failure cardiomyocytes, signaling pathways including SIK1/HDAC7, Wnt/β-catenin, and MAPK upregulate c-Myc expression. EZH2 enhances c-Myc protein stability by suppressing its ubiquitin-mediated degradation, thereby promoting inflammation, cardiac hypertrophy, and cardiac fibrosis. AMPK, adenosine monophosphate-activated protein kinase; EZH2, enhancer of zeste homolog 2; HDAC7, histone deacetylase 7; H3K27me3, histone H3 lysine 27 trimethylation; HUWE1, HECT, UBA and WWE domain containing 1; SIK1, salt-inducible kinase 1.

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  Figure 3. The role of c-Myc in energy metabolism in heart failure the c-Myc/MAX heterodimer fosters glycolysis by upregulating aldolase and pyruvate kinase expression. The c-Myc/HIF-1α transcriptional complex, assisted by lactylated NUSAP1, initiates high expression of LDHA, which expedites lactic acid production during glycolysis. In the resulting high-lactate environment, c-Myc may undergo lactylation modification, leading to enhanced activity, intracellular accumulation, and sustained oncogenic function. DHAP, dihydroxyacetone phosphate; HIF1-α, hypoxia-inducible factor 1-α; LDHA, lactate dehydrogenase A; MAX, MYC associated factor X; NADH, nicotinamide adenine dinucleotide; NUSAP1, nucleolar and spindle associated protein 1; PEP, phosphoenolpyruvate; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.

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  Figure 4. Role of c-Myc in cardiac regeneration and repair in heart failure overexpressed Snhg1 binds to PTEN and promotes its degradation, inhibiting c-Myc hydrolysis by enhancing Akt and PI3 K phosphorylation. Meanwhile, c-Myc, as a transcription factor, upregulates Snhg1 expression by binding to its promoter region, forming a positive feedback loop. This promotes cardiomyocyte division in neonatal mice and induces cell cycle re-entry in adult mice (evidenced by increased Edu+, PH3+, and AuroraB+ cells). Additionally, overexpression of circIGF1R, CNBP, Mydgf, and NASP upregulates c-Myc expression through the PI3 K/Akt and Wnt/β-catenin pathways, facilitating cell cycle re-entry. Akt, Ak strain transforming; AuroraB, aurora kinase B; circIGF1R, circular insulin-like growth factor 1 receptor; CNBP, cellular nucleic acid-binding protein; Mydgf, myeloid-derived growth factor; NASP, nuclear autoantigenic sperm protein; pdgfrβ, platelet-derived growth factor receptor β; PH, pleckstrin homology domain; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Snhg1, small nucleolar RNA host gene 1.

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  Figure 5. Differential roles of C–Myc in HFrEF and HFpEF. In HFrEF, c-Myc promotes cardiac remodeling, fibrosis, and metabolic dysregulation, while potentially suppressing HFrEF through cardiac repair and alleviation of drug-induced cardiomyopathy. In HFpEF, c-Myc might drive insulin resistance, metabolic inflammation, and fibrosis, thereby promoting HFpEF progression, while potentially counteracting HFpEF by protecting against coronary microvascular endothelial dysfunction.

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  Figure 6. Mechanisms of Action of Traditional Chinese Medicine in Inhibiting c-Myc Linggui Zhugan Decoction, Qishen Granules, and monomers Leonurine or Diacerein downregulate c-Myc by inhibiting the Wnt/β-catenin and MAPK pathways, and consequently alleviate cardiac hypertrophy, fibrosis, and inflammation in heart failure. AngII, angiotensin II; AT1, angiotensin ii receptor type 1; EPK, extracellular signal-regulated kinase; FZD, frizzled; Dvl, Dishevelled; JNK, c-Jun N-Terminal Kinase; LGZG, Linggui Zhugan Decoction; MAPKs, mitogen-activated protein kinases; P38, p38 mitogen-activated protein kinase; QSG, qishen granule; TCF-LEF, T cell factor - lymphoid enhancer-binding factor.