The ubiquitin system in heart and vessel pathobiology: From mechanisms to therapeutic strategies

Figures

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  Figure 1. Timeline of the research process on ubiquitination.7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22

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  Figure 2. The regulatory process of ubiquitination. The ubiquitin molecule activates E1 in an ATP-consuming manner to form the E1-ubiquitin intermediate. Subsequently, the ubiquitin molecule transfers from E1 to the E2 enzyme to create the E2-ubiquitin intermediate. Finally, the E3 ligase binds to the target protein, leading to the formation of the ubiquitin-tagged target protein. Two types of E3 ligases are involved in this process: RING and U-box-type E3, which transfer to substrate proteins through an intermediate complex of E3 and E2-Ub, and RBR and HECT-type E3, where E2-Ub interacts to transfer ubiquitin to E3, which in turn transfers ubiquitin to the substrate. Ubiquitin chains linked by K48 and K11 facilitate the direct degradation of substrates in the proteasome, while mono-ubiquitinated and K63-linked ubiquitin chains serve non-protein hydrolytic functions. E1, ubiquitin-activating enzyme; E2, ubiquitin-conjuating enzyme; E3, ubiquitin ligases; Ub, ubiquitin; Dub, deubiquitinase.

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  Figure 3. The role of ubiquitination in cardiovascular disease. The role of ubiquitination in cardiovascular disease spans across various conditions, including atherosclerosis, ischemia–reperfusion injury, cardiac remodeling, hypertension, and arrhythmias, regulating different cellular functions and signaling in different diseases. MI/R, myocardial ischemia–reperfusion. Created with Adobe Illustrator.

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  Figure 4. Regulatory targets of ubiquitination in atherosclerosis. Ubiquitination regulates homeostatic balance of proteins in endothelial cells (A), macrophage inflammation (B), and smooth muscle phenotypic (C). WWP2, MDM2, TRIM64, TRIM37, and epsin are E3 ubiquitin ligases. USP11 and UCHL1 are deubiquitinases. VSMCs, vascular smooth muscle cells; Septin4, endothelial injury factor; RXRβ, retinoid X receptor-like β; MYJ, modified Yuejuwan (a traditional Chinese medicine); IDO1, indoleamine 2,3-dioxygenase 1; MSI2, Musashi-2 (a binding protein); LRP-1, low-density lipoprotein receptor-related protein 1; CTRP9, C1q/TNF-related protein 9.

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  Figure 5. Regulatory targets of ubiquitination in MI/RI. In cardiomyocytes, cell death can occur through processes such as autophagy, necrosis, apoptosis, and ferroptosis. The E3 ubiquitin ligase has been identified as a key player in promoting cardiomyocyte death. Additionally, deubiquitinating enzymes are involved in mediating ferroptosis in cardiomyocytes through various signaling pathways. MI/RI, myocardial ischemia–reperfusion injury; Atrogin-1, MuRF1, TRIM32, and NEDD4L are E3 ubiquitin ligases; USP22 and USP11 are deubiquitinating enzymes. c-Cbl, the proto-oncogene Casita b-lineage lymphoma; YAP, yes-associated protein; Alox15, 15-lipoxygenase; RNF34, ring finger protein 34; 15-HpETE, 15-hydroperoxyeicosatetraenoic acid; ACSL4, acyl-CoA synthetase long-chain family member 4; Pgc1α, proliferator-activated receptor gamma coactivator 1-alpha.

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  Figure 6. Regulatory targets of ubiquitination in cardiac remodeling. Ubiquitination plays a crucial role in cardiac remodeling by regulating various cellular functions and signaling pathways, such as cardiomyocyte hypertrophy (A), fibroblast activation (B), and mitochondrial function (C). Tom20, Mfn1, and Mfn2 indicate the outer membrane of mitochondria. CnA, calmodulin A; JNK1/2, c-Jun N-terminal kinase; Ub, ubiquitin; HIF1α, hypoxia-inducible factor 1 alpha; HIF2α, hypoxia-inducible factor 2 alpha; SRF, serum-response factor; Mfn2, mitofusin2; PPARα, peroxisome proliferator-activated receptor α; TRIM, tripartite motif containing 44; TAK1, transforming growth factor-β-activated kinase 1; PFKFB3, phosphofructokinase-2/fructose-2,6-bisphosphatase 3; OTUD4, deubiquitinase OTU domain containing 4; Pellino 1, a member of the Pelle-interacting protein family; Parkin, parkin RBR E3 ubiquitin-protein ligase; Pink1, PTEN induced putative kinase 1; Shank3, SH3 and multiple ankyrin repeat domains protein 3; CaMKII, Ca2+/calmodulin-dependent protein kinase II; FUNDC1, FUN14 domain containing 1; LC3, light chain 3.

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  Figure 7. Roles of ubiquitination in regulating cardiac arrhythmia and hypertension. (A) Ubiquitination regulates ion channel proteins in cardiac arrhythmia. Normal cardiac rhythms rely on the coordinated function of cardiac ion channels. The protein Na(V)1.5 is encoded by the SCN5A gene. The E3 ubiquitin ligase CDC20 mediates ubiquitination of the transcription factor Meis1, which inhibits transcription of SCN5A and leads to arrhythmia. FAT10 binds to Kv7.1, preventing its ubiquitination and mitigating arrhythmia. (B) Ubiquitination regulates signaling pathways in hypertension. Mutations in Cullin 3 cause hypertension. The E3 ubiquitin ligases WWP2 and Nedd4L, and dysregulation of T lymphocytes can contribute to the development of hypertension. SCN5A, sodium voltage-gated channel alpha subunit 5; Nedd4L, NEDD4-like E3 ubiquitin protein ligase; CDC20, cell division cycle 20 homologue; FAT10, human HLA-F-adjacent transcript; Ub, ubiquitin; Cullin 3, subunits of the CUL3-RING (CRL3) ubiquitin ligase complex; ACE2, angiotensin converting enzyme 2; Ubr1, ubiquitin protein ligase E3 component N-recognin 1; Ac, acetylation; P, phosphorylation.