Reactive Oxygen Species in Thoracic Aortic Dissection: Insights into Mechanisms and Disease Progression

Figures

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  Fig. 1. ROS generation and signaling networks driving thoracic aortic dissection (TAD). ROS are generated in the aortic wall primarily through NOX, iNOS, eNOS uncoupling, and mitochondrial dysfunction. Excessive ROS accumulation promotes oxidative stress and activates multiple ROS-mediated pathways, including MAPK, inflammatory, metabolic, and redox-sensitive signaling. These pathways contribute to key pathological changes in the aortic wall, including ECM remodeling, VSMC apoptosis and phenotypic switching, endothelial dysfunction, and inflammatory cell infiltration. Collectively, these alterations lead to aortic wall destabilization in TAD. In addition, a positive feedback loop is formed, in which aortic wall injury further enhances ROS production through NOX activation and mitochondrial ROS generation, thereby amplifying oxidative stress.

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  Fig. 2. Multilevel regulation of ROS generation during the pathogenesis of thoracic aortic dissection (TAD). ROS production in TAD is regulated by integrated signaling, metabolic, and epigenetic mechanisms across ECs, VSMCs, and infiltrating immune cells. Pro-inflammatory signaling pathways, including NF-κB, MAPK (p38/ERK1/2), and PKC, promote NOX activation through p47phox phosphorylation and enhance mitochondrial ROS generation. Metabolic dysregulation further amplifies oxidative stress, as abnormal glucose metabolism activates the AGE–RAGE–MAPK axis, while lipid overload and free fatty acid oxidation contribute to mitochondrial dysfunction and ER stress. Epigenetic regulators, including histone deacetylases, SIRT1, and ROS-responsive microRNAs, modulate redox homeostasis by influencing NOX activity, antioxidant capacity, and mitochondrial function. Crosstalk between metabolic stress and inflammation promotes macrophage M1 polarization, NET formation, and sustained ROS amplification. Together, these interconnected pathways establish a redox network that drives oxidative stress and vascular injury during TAD progression Abbreviations: PI3K, phosphoinositide 3-kinase; MAPK,…

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  Fig. 3. ROS-mediated regulation of cell fate during thoracic aortic dissection (TAD). Excessive ROS accumulation in the dissected aortic wall regulates multiple cell fate programs in ECs and VSMCs, including apoptosis, autophagy, and ferroptosis. ROS activate extrinsic apoptotic pathways through death receptors such as Fas and TRAIL-R, leading to caspase activation, while simultaneously promoting intrinsic mitochondrial apoptosis via JNK signaling, mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and NF-κB–dependent stress responses. ROS-induced endoplasmic reticulum stress, mediated by the PERK–CHOP axis, further amplifies apoptotic signaling. In parallel, ROS modulate autophagy through AMPK–mTOR–ULK1 signaling and interactions with BCL-2 and BECN1, influencing cellular survival or death depending on stress magnitude. In addition, lipid peroxidation and impaired antioxidant defenses, characterized by GPX4 inactivation, SLC7A11 dysfunction, glutathione depletion, and ACSL4 activation, sensitize vascular cells to ferroptosis. Collectively, ROS-driven dysregulation of apoptosis, autophagy, and ferroptosis contributes to VSMC injury, endothelial dysfunction, and…

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  Fig. 4. ROS-targeted therapeutic strategies and translational challenges in thoracic aortic dissection (TAD). (A) Inhibition of ROS-generating enzymes. Pathological ROS production can be attenuated by targeting upstream enzymatic sources, particularly NOX, using isoform-selective inhibitors, genetic knockdown, or natural compounds, as well as by mitigating pathological eNOS uncoupling to reduce superoxide generation. (B) Antioxidant interventions. Strategies aimed at enhancing antioxidant capacity include exogenous antioxidants such as polyphenols and vitamin C, as well as reinforcement of endogenous antioxidant systems involving glutathione, cysteine availability, and SOD mimetics. (C) Targeting ROS-related signaling pathways. Pharmacological and natural agents modulate downstream redox-sensitive pathways, including NF-κB, MAPK/JNK, and AGE–RAGE–MAPK signaling, as well as MMP activation, thereby attenuating inflammation, extracellular matrix degradation, and vascular remodeling. (D) Modulation of metabolic reprogramming. Therapeutic approaches targeting metabolic dysregulation aim to restore mitochondrial function, enhance fatty acid oxidation, suppress pathological glycolytic shifts,…