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Targeting autophagy to treat neointimal hyperplasia in vascular disease

Year: 2025

Type: editorial

Abstract: This editorial refers to ‘Novel roles of Nrf3-Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia’ by Q. Chen et al., https://doi.org/10.1093/cvr/cvaf084. Neointimal hyperplasia is a maladaptive response to vascular injury characterized by a pathologic thickening of the intimal layer of blood vessels. It is caused by multiple factors, including mechanical damage from interventional procedures, inflammatory responses within the vascular wall, haemodynamic changes, diabetes mellitus, and dyslipidemia.1 Neointimal hyperplasia appears in a variety of vascular diseases including atherosclerosis, post-stent restenosis, vascular graft disease, transplant vasculopathy, arteriovenous fistula disease, hypertensive vascular disease or vasculitis. In all these conditions, neointimal hyperplasia contributes to luminal narrowing, which impairs blood flow and can lead to ischaemic complications in the affected tissue or organ.1 At the cellular level, neointimal hyperplasia is driven by pathological alterations in vascular smooth muscle cell (VSMC) function. VSMCs, typically located within the media layer of blood vessels, are pivotal to vascular homeostasis, regulating vascular tone, blood pressure, and blood flow distribution.2 Under physiological conditions, VSMCs maintain a differentiated, contractile phenotype, marked by high contractile strength and low proliferative and migratory capabilities. However, under stressors such as hypoxia, inflammation, and haemodynamic changes, VSMCs transition into a synthetic, proliferative state, producing extracellular matrix components, secreting proinflammatory cytokines, recruiting immune cells, and exacerbating vascular inflammation.2 Their enhanced proliferative capacity results in vascular wall thickening, luminal stenosis, and progression toward atherosclerosis, arterial restenosis, or vascular lumen narrowing in various vascular beds.3 Autophagy (from the Greek for ‘self-eating’) is a tightly regulated cellular degradation and recycling process. It eliminates damaged organelles, misfolded proteins, and harmful cellular debris through the formation of autophagosomes, which fuse with lysosomes for breakdown and recycling. This process maintains cellular homeostasis under normal conditions and acts as a survival mechanism during nutrient deprivation, hypoxia, metabolic, inflammatory, haemodynamic, or oxidative stress.4 Defective autophagy has therefore been implicated in the pathogenesis of several vascular diseases.5 Indeed, autophagy is a critical determinant of VSMC plasticity and phenotypic switching. While physiological autophagy promotes VSMC survival, impaired or excessive autophagy may lead to cell death, neointimal formation and atherosclerotic plaque instability.5 Given that autophagy in VSMCs is essential for maintaining vascular integrity, a deeper understanding of its mechanisms is crucial to uncover novel therapeutic targets for neointimal hyperplasia. In this issue of Cardiovascular Research, Chen et al.6 aim to investigate the potential role of NRF3 in neointimal hyperplasia. NRF3 is a member of the Cap'n'Collar family and is a basic leucine zipper transcription factor.7 While NRF2, and to a lesser extent NRF1, protective roles have been widely characterized in cardiovascular homeostasis, NRF3 has received very limited attention. Current understanding of NRF3 remains largely confined to its transcriptional roles in carcinogenesis, where it contributes to cancer cell viability through the regulation of autophagy.8 In the present study, the authors first showed an increased NRF3 expression in both human carotid and femoral atherosclerotic lesions, which was associated with VSMCs phenotypic switch to a synthetic and inflammatory phenotype, and with the extent of vascular remodelling.6 Then, they reported that NRF3 knockdown decreased proliferation, migration, and inflammatory responses of human and murine VSMCs under PDGF-BB, TNF-α, and ox-LDL pathological stimuli. Mechanistically, these stimuli caused endoplasmic reticulum stress response marked by an increase of ATF4. ATF4 transcriptionally activates NRF3, triggering its upregulation to induce TRIM5 expression, a recently identified genetic risk locus for coronary artery disease, and promoted TRIM5/BECN1-induced VSMC autophagy in response to pathological stimuli or vascular injury.6 Subsequently, the authors performed wire injury or ligation-induced neointimal hyperplasia in VSMC-specific NRF3 knockout and in NRF3 global knockout mice. Genetic deletion of NRF3 decreases neointimal hyperplasia and reduces VSMC accumulation and inflammation levels. Restoration of NRF3 expression in the vascular wall using an AAV9 delivery system in NRF3 global knockout mice increased the neointimal area, which was prevented by administration of the autophagy inhibitor chloroquine, confirming the critical for autophagy in NRF3-mediated VSMC proliferation and migration.6 Nonetheless, NRF3 overexpression was also observed in the liver, suggesting a potential off-target effect in the gene delivery system used. Finally, moving beyond the murine models, the authors administered AAV9-shNrf3-mediated targeted suppression of NRF3 to a porcine model of carotid artery stenting. They showed decreased neointimal hyperplasia, reduced vascular inflammation, and reduction of TRIM5, thereby demonstrating the therapeutic translational of targeting NRF3 relevance for restenosis intervention (Figure 1).6 Although autophagy modulators show promise across diverse clinical disorders, none were specifically designed to regulate autophagy in human vascular diseases. Indeed, existing drugs like rapamycin, a potent inducer of autophagy, and chloroquine, an autophagy inhibitor, were originally developed for other purposes leading to a lack of specificity.4 Chronic rapamycin use suppresses mTORC2 signalling, causing immunosuppression, while chloroquine disrupts lysosomal function, impairing both autophagy and endosomal trafficking, alongside unrelated immunomodulatory and antineoplastic effects.4 Furthermore, targeting autophagy demonstrates bidirectional therapeutic potential in vascular pathologies. While autophagy induction may protect against endothelial dysfunction and hypertension, autophagy-inducing stimuli promote VSMC proliferation, leading to vascular remodelling. In contrast, rapamycin-based drugs are used to treat arterial stenosis.5 Therefore, targeting autophagy requires caution to avoid adverse effects, and there is a crucial need to understand the role and the form of autophagy at different vascular disease stages for effective treatment. In that view, NRF3 emerges as an attractive therapeutic target due to its context-dependent and tissue-specific behaviour. Unlike its broadly expressed counterparts NRF1 and NRF2, NRF3 displays uneven tissue distribution. NRF3 global knockout mice displayed no phenotype under physiological conditions, and there is no compensatory effect of NRF1 and NRF2 in NRF3 knockout mice,6 indicating that inhibiting NRF3 may have a favourable safety profile. Moreover, NRF3 drive a more selective transcriptional programme,7 a feature that could potentially reduce off-target effects. While NRF3 has been shown to promote embryonic stem cell differentiation toward contractile SMCs,9 it promotes VSMC proliferation and migration under atherogenic stress.6 Similarly, increased NRF3 expression in response to cardiac injury promotes cardiomyocyte apoptosis and contributes to adverse cardiac remodelling,10 confirming a role for NRF3 in driving disease-related phenotype upon pathological stimulation. Overall, the newly discovered NRF3–TRIM5 axis in regulating autophagy in VSMCs provides a new direction for developing treatments for neointimal hyperplasia-related diseases. The NRF3-TRIM5 axis promotes vascular smooth muscle cell autophagy. Pathological stimuli (TNF-α, ox-LDL, PDGF-BB, FBS) or mouse models of neointimal hyperplasia induce endoplasmic reticulum stress in vascular smooth muscle cells, leading to ATF4 upregulation. ATF4 transcriptionally activates NRF3, which subsequently enhances TRIM5 expression. TRIM5 recruits BECN1 and assembles a functional complex to initiate autophagosome formation. This autophagy activation promotes vascular smooth muscle cell phenotypic switching, characterized by enhanced proliferation, migration, and inflammation, ultimately driving neointimal hyperplasia. Figure created with Biorender: https://BioRender.com/it5u2ee. R.Y. is supported by China Scholarship Council. S.T.-C. is supported by grants from the British Heart Foundation grant (PG/23/11093) and the Royal Society (RG\R1\241197). K.S. has been supported by grants from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (MODVASC, grant agreement no. 759248), the German Research Foundation Deutsche Forschungsgemeinschaft (DFG) (CRC1366 C07, project no. 394046768), the Health + Life Science Alliance Heidelberg Mannheim, and the Helmholtz Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at the Heidelberg University.

Source: Cardiovascular Research

DOI: 10.1093/cvr/cvaf104

Authors: Runan Yan, Simon Tual-Chalot, Konstantinos Stellos