Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection
摘要: 胸主动脉夹层是一种高致死率（65%～85%）的心血管疾病。外科手术辅助植/介入支架是治疗胸主动脉夹层的主要方式，但手术治疗会引起严重的术后并发症，患者术后具有较高的死亡风险。由于其发病机制尚不清楚，故缺乏有效的药物治疗策略。近年来，随着单细胞测序等新技术的发展，初步证实血管平滑肌细胞的功能紊乱在胸主动脉夹层发生发展过程中起着特殊作用。目前，调控血管平滑肌细胞功能紊乱的分子机制已得到初步研究，相关成果可望为寻找潜在的药物治疗靶点提供新思路，有助于开发防治胸主动脉夹层的新策略。本文总结了血管平滑肌细胞功能失衡在胸主动脉夹层发生发展过程中的重要作用，详细介绍了调控血管平滑肌细胞功能紊乱的生物因素及相关分子机制，为明确血管平滑肌细胞功能紊乱在胸主动脉夹层发生发展过程中的核心地位以及寻找有效的药物分子靶标提供参考依据。Abstract: Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.
Category Gene Key functions Consequences of mutations Genes associated with contraction, differentiation, and proliferation of VSMCs MYH11 Encoding smooth muscle myosin heavy chain and involvement in smooth muscle cell contraction Familial thoracic aortic aneurysm and increased risk of dissection in the thoracic aorta MYLK Encoding myosin light chain kinase and involvement in smooth muscle cell contraction Familial thoracic aortic aneurysm and dissection PRKG1 Encoding type Ⅰ cyclic GMP-dependent protein kinase, which controls smooth muscle cell relaxation Association with thoracic aortic aneurysm and acute aortic dissection FLNA Encoding filamin-A and involvement in smooth muscle cell contraction Cardiac valvular dysplasia MAT2A Encodeing the enzyme MAT Ⅱa Association with thoracic aortic aneurysm FOXE3 Encoding a transcription factor involved in cellular differentiation Increased risk of aortic dissection Extracellular matrix-associated genes LOX Encoding the majority of lysyl oxidase in the aorta Marfan syndrome and increases in aortic aneurysm and dissections FBN1 Encoding fibrillin 1 and formation of microfibrils Marfan syndrome FBN2 Encoding fibrillin 2 and formation of microfibrils Marfan syndrome and aortic root dilatation COL3A1 Encoding type Ⅲ collagen and synthesis of extracellular matrix collagen Vascular Ehlers-Danlos syndrome and increased risk of dissection in the thoracic aorta COL5A1 Encoding type Ⅴ collagen and synthesis of extracellular matrix collagen Vascular Ehlers-Danlos syndrome COL1A2 Encoding type Ⅰ collagen and synthesis of extracellular matrix collagen Vascular Ehlers-Danlos syndrome and aortic regurgitation MFAP5 Encoding structural proteins of elastin fibres and microfibrils Increased risk of aortic dissection TGF-β signalling pathway and its associated receptor protein genes TGF-βR1&TGF-βR2 Encoding receptors involved in TGFβ signalling Loeys-Dietz syndrome and increased risk of dissection in the thoracic aorta SMAD2 &SMAD3&SMAD4 Modulating transcription factors involved with the extracellular matrix Increased risk of dissection MYH11: myosin heavy chain 11; MYLK: myosin light chain kinase; PRKG1: protein kinase c GMP-dependent 1; FLNA: filamin A; MAT2A: methionine adenosyltransferase 2A; FOXE3: forkhead box protein E3; LOX: lysyl oxidase; FBN: fibrillin; COL3A1: collagen type Ⅲ, alpha-1 chain; COL5A1: collagen type Ⅴ, alpha-1 chain; COL1A2: collagen type Ⅰ, alpha-2 chain; MFAP5: microfibrillar-associated protein 5; TGF-βR: transforming growth factor-beta receptor; SMAD: mothers against decapentaplegic homolog.
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