Advances in molecular mechanisms and therapeutic targets for aortic dissection_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

TANGJIAREKE ¹ , ABUDUREHEMAN·Wubulaximu ² , GUAN Sheng ² , ZULIKAIER·Ainiwa ² ,  GE Xiaohu ²

1. Graduate School of Xinjiang Medical University, Urumqi 830017, P. R. China;
2. Department of Cardiac Surgery, Xinjiang Uygur Autonomous Region People’s Hospital, Urumqi 830001, P. R. China;

Corresponding?author：

GE Xiaohu, Email: gexiaohu_xj@163.com

Keywords：

aortic dissection; molecular mechanism; vascular senescence

DOI：

10.7507/1007-9424.202505116

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the pivotal role and key molecular mechanisms of aortic dissection (AD) pathogenesis, providing novel perspectives for early diagnosis and treatment. Methods The relevant literature on domestic and foreign research in recent years was summarized. Results Vascular aging constitutes a fundamental pathological basis for AD, genic abnormalities (e.g., Gene 33, CEBPB, IGFBP-3) and signal pathway dysregulation(e.g., Notch, ferroptosis) are important to genesis of AD. Conclusion AD pathogenesis is intimately linked to vascular aging. Targeting aging-associated genes or pathways may emerge as innovative strategies for AD prevention and management. Further clinical translational research is warranted to establish the safety and therapeutic efficacy.

Citation： TANGJIAREKE, ABUDUREHEMAN·Wubulaximu, GUAN Sheng, ZULIKAIER·Ainiwa, GE Xiaohu. Advances in molecular mechanisms and therapeutic targets for aortic dissection. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(3): 421-424. doi: 10.7507/1007-9424.202505116 Copy

1.	Yin ZQ, Han H, Yan X, et al. Research progress on the pathogenesis of aortic dissection. Curr Probl Cardiol, 2023, 48(8): 101249. doi: 10.1016/j.cpcardiol.2022.101249.
2.	Tao Y, Li G, Yang Y, et al. Epigenomics in aortic dissection: from mechanism to therapeutics. Life Sci, 2023, 335: 122249. doi: 10.1016/j.lfs.2023.122249.
3.	Gasser S, Stastny L, Kofler M, et al. Rapid response in type A aortic dissection: is there a decisive time interval for surgical repair? Thorac Cardiovasc Surg, 2021, 69(1): 49-56.
4.	Yang M. Acute Lung Injury in aortic dissection: new insights in anesthetic management strategies. J Cardiothorac Surg, 2023, 18(1): 147. doi: 10.1186/s13019-023-02223-3.
5.	Carbone A, Palladino R, Franzese M, et al. Health-related quality of life in patients with aortic dissection: an unmet need. Curr Probl Cardiol, 2024, 49(1 Pt C): 102138. doi: 10.1016/j.cpcardiol.2023.102138.
6.	Harris KM, Nienaber CA, Peterson MD, et al. Early mortality in type A acute aortic dissection: insights from the international registry of acute aortic dissection. JAMA Cardiol, 2022, 7(10): 1009-1015.
7.	Cong X, Kong W. Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease. Cell Signal, 2020, 66: 109485. doi: 10.1016/j.cellsig.2019.109485.
8.	Luo S, Kong C, Zhao S, et al. Endothelial HDAC1-ZEB2-NuRD complex drives aortic aneurysm and dissection through regulation of protein S-sulfhydration. Circulation, 2023, 147(18): 1382-1403.
9.	Islam T. Impact of statins on vascular smooth muscle cells and relevance to atherosclerosis. J Physiol, 2020, 598(12): 2295-2296.
10.	Dookun E, Walaszczyk A, Redgrave R, et al. Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery. Aging Cell, 2020, 19(10): e13249. doi: 10.1111/acel.13249.
11.	Lawrie A, Francis SE. Frataxin and endothelial cell senescence in pulmonary hypertension. J Clin Invest, 2021, 131(11): e149721. doi: 10.1172/JCI149721.
12.	Bloom SI, Islam MT, Lesniewski LA, et al. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol, 2023, 20(1): 38-51.
13.	Viereck J, Thum T. Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury. Circ Res, 2017, 120(2): 381-399.
14.	Lee KL, Isham KR, Stringfellow L, et al. Molecular cloning of cDNAs cognate to genes sensitive to hormonal control in rat liver. J Biol Chem, 1985, 260(30): 16433-16438.
15.	Messina JL. Regulation of gene expression by insulin. Handbook of Experimental Pharmacology, Vol. 92: Insulin. Springer-Verlag; NY: 1990. pp. 263-281.
16.	Wick M, Bürger C, Funk M, et al. Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. Exp Cell Res, 1995, 219(2): 527-535.
17.	Makkinje A, Quinn DA, Chen A, et al. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J Biol Chem, 2000, 275(23): 17838-17847.
18.	Cadilla C, Isham KR, Lee KL, et al. Insulin increases transcription of rat gene 33 through cis-acting elements in 5’-flanking DNA. Gene, 1992, 118(2): 223-229.
19.	Kent TA, Messina JL, Weinstock RS, et al. Synergistic induction of gene 33 expression by retinoic acid and insulin. Endocrinology, 1994, 134(5): 2237-2244.
20.	Romero N, Jiménez BD, Cadilla CL. Insulin and phorbol ester regulation of gene 33 expression in CHO cells. P R Health Sci J, 1999, 18(3): 257-265.
21.	Varley CL, Armitage S, Dickson AJ. Activation of stress-activated protein kinases by hepatocyte isolation induces gene 33 expression. Biochem Biophys Res Commun, 1999, 254(3): 728-733.
22.	Xu D, Makkinje A, Kyriakis JM. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem, 2005, 280(4): 2924-2933.
23.	Mohn KL, Laz TM, Melby AE, et al. Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. J Biol Chem, 1990, 265(35): 21914-21921.
24.	Descot A, Hoffmann R, Shaposhnikov D, et al. Negative regulation of the EGFR-MAPK cascade by actin-MAL-mediated Mig6/Errfi-1 induction. Mol Cell, 2009, 35(3): 291-304.
25.	Chu DT, Davis CM, Chrapkiewicz NB. Reciprocal regulation of gene transcription by insulin. Inhibition of the phosphoenolpyruvate carboxykinase gene and stimulation of gene 33 in a single cell type. J Biol Chem, 1988, 263(26): 13007-13011.
26.	Meléndez PA, Longo N, Jimenez BD, et al. Insulin-induced gene 33 mRNA expression in Chinese hamster ovary cells is insulin receptor dependent, J Cell Biochem, 2000, 77(3): 432-444.
27.	Weinstock RS, Messina JL. Vanadate and insulin stimulate gene 33 expression. Biochem Biophys Res Commun, 1992, 189(2): 931-937.
28.	Jeong JW, Lee HS, Lee KY, et al. Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease. Proc Natl Acad Sci U S A, 2009, 106(21): 8677-8682.
29.	Cai J, Yi FF, Yang L, et al. Targeted expression of receptor-associated late transducer inhibits maladaptive hypertrophy via blocking epidermal growth factor receptor signaling. Hypertension, 2009, 53(3): 539-548.
30.	Wang ND, Finegold MJ, Bradley A, et al. Impaired energy homeostasis in C/EBP alpha knockout mice. Science, 1995, 269(5227): 1108-1112.
31.	Bassères DS, Levantini E, Ji H, et al. Respiratory failure due to differentiation arrest and expansion of alveolar cells following lung-specific loss of the transcription factor C/EBPalpha in mice. Mol Cell Biol, 2006, 26(3): 1109-1123.
32.	Heath V, Suh HC, Holman M, et al. C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood, 2004, 104(6): 1639-1647.
33.	Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A, 1997, 94(2): 569-574.
34.	Screpanti I, Romani L, Musiani P, et al. Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J, 1995, 14(9): 1932-1941.
35.	Rahman SM, Janssen RC, Choudhury M, et al. CCAAT/enhancer-binding protein β (C/EBPβ) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice. J Biol Chem, 2012, 287(41): 34349-34360.
36.	Zhu S, Oh HS, Shim M, et al. C/EBPbeta modulates the early events of keratinocyte differentiation involving growth arrest and keratin 1 and keratin 10 expression. Mol Cell Biol, 1999, 19(10): 7181-7190.
37.	Chen SS, Chen JF, Johnson PF, et al. C/EBPbeta, when expressed from the C/ebpalpha gene locus, can functionally replace C/EBPalpha in liver but not in adipose tissue. Mol Cell Biol, 2000, 20(19): 7292-7299.
38.	Chiu CH, Lin WD, Huang SY, et al. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev, 2004, 18(16): 1970-1975.
39.	López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell, 2013, 153(6): 1194-1217.
40.	Hartell NA, Archer HE, Bailey CJ, et al. Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol, 2005, 69(5): 781-790.
41.	Albrethsen J, Drici L, Slot Vilmann LM, et al. Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS. Clin Chem Lab Med, 2025, 63(8): 1528-1537.
42.	阿希, 周梅, 劉燕. 基于平滑肌細胞衰老探討Notch信號通路在小鼠胸主動脈夾層形成中的作用. 中國心血管病研究, 2023, 21(8): 728-734.
43.	Zou S, Ren P, Nguyen M, et al. Notch signaling in descending thoracic aortic aneurysm and dissection. PLoS One, 2012, 7(12): e52833. doi: 10.1371/journal.pone.0052833.
44.	Luo Y, Luo J, An P, et al. The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture. Eur Heart J, 2024, 45(4): 287-305.
45.	Sun DY, Wu WB, Wu JJ, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nat Commun, 2024, 15(1): 1429. doi: 10.1038/s41467-024-45823-w.

1. Yin ZQ, Han H, Yan X, et al. Research progress on the pathogenesis of aortic dissection. Curr Probl Cardiol, 2023, 48(8): 101249. doi: 10.1016/j.cpcardiol.2022.101249.
2. Tao Y, Li G, Yang Y, et al. Epigenomics in aortic dissection: from mechanism to therapeutics. Life Sci, 2023, 335: 122249. doi: 10.1016/j.lfs.2023.122249.
3. Gasser S, Stastny L, Kofler M, et al. Rapid response in type A aortic dissection: is there a decisive time interval for surgical repair? Thorac Cardiovasc Surg, 2021, 69(1): 49-56.
4. Yang M. Acute Lung Injury in aortic dissection: new insights in anesthetic management strategies. J Cardiothorac Surg, 2023, 18(1): 147. doi: 10.1186/s13019-023-02223-3.
5. Carbone A, Palladino R, Franzese M, et al. Health-related quality of life in patients with aortic dissection: an unmet need. Curr Probl Cardiol, 2024, 49(1 Pt C): 102138. doi: 10.1016/j.cpcardiol.2023.102138.
6. Harris KM, Nienaber CA, Peterson MD, et al. Early mortality in type A acute aortic dissection: insights from the international registry of acute aortic dissection. JAMA Cardiol, 2022, 7(10): 1009-1015.
7. Cong X, Kong W. Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease. Cell Signal, 2020, 66: 109485. doi: 10.1016/j.cellsig.2019.109485.
8. Luo S, Kong C, Zhao S, et al. Endothelial HDAC1-ZEB2-NuRD complex drives aortic aneurysm and dissection through regulation of protein S-sulfhydration. Circulation, 2023, 147(18): 1382-1403.
9. Islam T. Impact of statins on vascular smooth muscle cells and relevance to atherosclerosis. J Physiol, 2020, 598(12): 2295-2296.
10. Dookun E, Walaszczyk A, Redgrave R, et al. Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery. Aging Cell, 2020, 19(10): e13249. doi: 10.1111/acel.13249.
11. Lawrie A, Francis SE. Frataxin and endothelial cell senescence in pulmonary hypertension. J Clin Invest, 2021, 131(11): e149721. doi: 10.1172/JCI149721.
12. Bloom SI, Islam MT, Lesniewski LA, et al. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol, 2023, 20(1): 38-51.
13. Viereck J, Thum T. Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury. Circ Res, 2017, 120(2): 381-399.
14. Lee KL, Isham KR, Stringfellow L, et al. Molecular cloning of cDNAs cognate to genes sensitive to hormonal control in rat liver. J Biol Chem, 1985, 260(30): 16433-16438.
15. Messina JL. Regulation of gene expression by insulin. Handbook of Experimental Pharmacology, Vol. 92: Insulin. Springer-Verlag; NY: 1990. pp. 263-281.
16. Wick M, Bürger C, Funk M, et al. Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. Exp Cell Res, 1995, 219(2): 527-535.
17. Makkinje A, Quinn DA, Chen A, et al. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J Biol Chem, 2000, 275(23): 17838-17847.
18. Cadilla C, Isham KR, Lee KL, et al. Insulin increases transcription of rat gene 33 through cis-acting elements in 5’-flanking DNA. Gene, 1992, 118(2): 223-229.
19. Kent TA, Messina JL, Weinstock RS, et al. Synergistic induction of gene 33 expression by retinoic acid and insulin. Endocrinology, 1994, 134(5): 2237-2244.
20. Romero N, Jiménez BD, Cadilla CL. Insulin and phorbol ester regulation of gene 33 expression in CHO cells. P R Health Sci J, 1999, 18(3): 257-265.
21. Varley CL, Armitage S, Dickson AJ. Activation of stress-activated protein kinases by hepatocyte isolation induces gene 33 expression. Biochem Biophys Res Commun, 1999, 254(3): 728-733.
22. Xu D, Makkinje A, Kyriakis JM. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem, 2005, 280(4): 2924-2933.
23. Mohn KL, Laz TM, Melby AE, et al. Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. J Biol Chem, 1990, 265(35): 21914-21921.
24. Descot A, Hoffmann R, Shaposhnikov D, et al. Negative regulation of the EGFR-MAPK cascade by actin-MAL-mediated Mig6/Errfi-1 induction. Mol Cell, 2009, 35(3): 291-304.
25. Chu DT, Davis CM, Chrapkiewicz NB. Reciprocal regulation of gene transcription by insulin. Inhibition of the phosphoenolpyruvate carboxykinase gene and stimulation of gene 33 in a single cell type. J Biol Chem, 1988, 263(26): 13007-13011.
26. Meléndez PA, Longo N, Jimenez BD, et al. Insulin-induced gene 33 mRNA expression in Chinese hamster ovary cells is insulin receptor dependent, J Cell Biochem, 2000, 77(3): 432-444.
27. Weinstock RS, Messina JL. Vanadate and insulin stimulate gene 33 expression. Biochem Biophys Res Commun, 1992, 189(2): 931-937.
28. Jeong JW, Lee HS, Lee KY, et al. Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease. Proc Natl Acad Sci U S A, 2009, 106(21): 8677-8682.
29. Cai J, Yi FF, Yang L, et al. Targeted expression of receptor-associated late transducer inhibits maladaptive hypertrophy via blocking epidermal growth factor receptor signaling. Hypertension, 2009, 53(3): 539-548.
30. Wang ND, Finegold MJ, Bradley A, et al. Impaired energy homeostasis in C/EBP alpha knockout mice. Science, 1995, 269(5227): 1108-1112.
31. Bassères DS, Levantini E, Ji H, et al. Respiratory failure due to differentiation arrest and expansion of alveolar cells following lung-specific loss of the transcription factor C/EBPalpha in mice. Mol Cell Biol, 2006, 26(3): 1109-1123.
32. Heath V, Suh HC, Holman M, et al. C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood, 2004, 104(6): 1639-1647.
33. Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A, 1997, 94(2): 569-574.
34. Screpanti I, Romani L, Musiani P, et al. Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J, 1995, 14(9): 1932-1941.
35. Rahman SM, Janssen RC, Choudhury M, et al. CCAAT/enhancer-binding protein β (C/EBPβ) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice. J Biol Chem, 2012, 287(41): 34349-34360.
36. Zhu S, Oh HS, Shim M, et al. C/EBPbeta modulates the early events of keratinocyte differentiation involving growth arrest and keratin 1 and keratin 10 expression. Mol Cell Biol, 1999, 19(10): 7181-7190.
37. Chen SS, Chen JF, Johnson PF, et al. C/EBPbeta, when expressed from the C/ebpalpha gene locus, can functionally replace C/EBPalpha in liver but not in adipose tissue. Mol Cell Biol, 2000, 20(19): 7292-7299.
38. Chiu CH, Lin WD, Huang SY, et al. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev, 2004, 18(16): 1970-1975.
39. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell, 2013, 153(6): 1194-1217.
40. Hartell NA, Archer HE, Bailey CJ, et al. Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol, 2005, 69(5): 781-790.
41. Albrethsen J, Drici L, Slot Vilmann LM, et al. Targeted proteomics of serum IGF-I, -II, IGFBP-2, -3, -4, -5, -6 and ALS. Clin Chem Lab Med, 2025, 63(8): 1528-1537.
42. 阿希, 周梅, 劉燕. 基于平滑肌細胞衰老探討Notch信號通路在小鼠胸主動脈夾層形成中的作用. 中國心血管病研究, 2023, 21(8): 728-734.
43. Zou S, Ren P, Nguyen M, et al. Notch signaling in descending thoracic aortic aneurysm and dissection. PLoS One, 2012, 7(12): e52833. doi: 10.1371/journal.pone.0052833.
44. Luo Y, Luo J, An P, et al. The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture. Eur Heart J, 2024, 45(4): 287-305.
45. Sun DY, Wu WB, Wu JJ, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nat Commun, 2024, 15(1): 1429. doi: 10.1038/s41467-024-45823-w.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Advances in molecular mechanisms and therapeutic targets for aortic dissection

Abstract Full text Figures/Tables Video References Cited by

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