Background: Oxidative stress plays critical pathophysiological roles in vascular remodeling-related cardiovascular diseases, including hypertension, atherosclerosis, and restenosis. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in cancer development and progression. However, the role of SENP3 in vascular remodeling remains unknown.Methods: We generated three mouse models of vascular remodeling due to low shear stress, hypertension, and atherosclerosis. The expression of SENP3 was determined by western blotting and/or immunofluorescence staining in cultured vascular smooth muscle cells (VSMCs), animal models, and human samples. The biological function of SENP3 in proliferation and migration of VSMC and vascular remodeling was further investigated in vitro and in vivo models.Findings: SENP3 was highly expressed in VSMCs of remodeled arteries, accompanied by elevated reactive oxygen species (ROS) levels. In cultured VSMCs, SENP3 protein levels were enhanced by oxidized low-density lipoprotein and Angiotensin II in a ROS-dependent manner. SENP3 overexpression significantly promoted and sh-RNA-mediated knockdown markedly inhibited VSMCs proliferation and migration. Immunofluorescence staining showed that SENP3 expression was correlated with intimal area in remodeled arteries. Furthermore, we demonstrated that SENP3 interacted with β-catenin and inhibited its proteasome-dependent degradation via de-SUMOylation of β-catenin. Most importantly, SENP3 + / − mice exhibited alleviated vascular remodeling.Interpretation: Our results highlight the important function of SENP3 as a redox sensor and mediator in vascular remodeling.
Background and Purpose Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor‐α (RXRα) is an intriguing anti‐atherosclerosis target. This study investigated whether and how an RXRα modulator, K‐80003, derived from a non‐steroidal anti‐inflammatory drug attenuates atherosclerotic plaque progression and destabilization. Experimental Approach Our previously established ApoE−/− mouse model of carotid vulnerable plaque progression was treated with K‐80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7‐ketocholesterol (7‐KC)‐stimulated macrophages treated with or without K‐80003. Key Results K‐80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF‐κB subunit were markedly reduced after K‐80003 treatment. Also, K‐80003 treatment inhibited 7‐KC‐induced p65 nuclear translocation, IκBα degradation, and transcription of NF‐κB target genes. In addition, K‐80003 inhibited NF‐κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K‐80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K‐80003 strongly inhibited 7‐KC‐induced RXRα cytoplasmic translocation. Conclusions and Implications K‐80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1‐mediated NF‐κB proinflammatory pathway. Thus, targeting RXRα‐mediated autophagy‐inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.
Xuezhikang (XZK), an extract of red yeast rice, is a traditional Chinese medicine widely used for the treatment of cardiovascular diseases in China and other countries. However, whether XZK treatment can improve atherosclerotic plaque stability is not fully understood. Based on our previously developed mouse model of spontaneous vulnerable plaque formation and rupture in carotid arteries in ApoE-/- mice. We showed that low-dose (600 mg/kg/d) XZK improved plaque stability without decreasing plaque area, whereas high-dose (1200 mg/kg/d) XZK dramatically inhibited vulnerable plaque progression accompanied by decreased plaque area. Mechanistically, XZK significantly suppressed lesional endoplasmic reticulum (ER) stress in mouse carotid arteries. In vitro, XZK inhibited 7-KC-induced activation of ER stress in RAW264.7 macrophages, as assessed by the reduced levels of p-PERK, p-IRE1α, p-eIF2α, c-ATF6, s-XBP1, and CHOP. Compared to controls, the XZK-treated group displayed dramatically decreased apoptotic cell numbers (shown by decreased TUNEL- and cleaved caspase3-positive cells), lower necrotic core area and ratio, and reduced expression of NF-κB target gene. In RAW264.7 cells, XZK inhibited 7-KC-induced upregulation of apoptosis, protein expression of apoptotic markers (cleaved caspase-3 and cleaved PARP), and NF-κB activation (shown by target gene transcription and IκBα reduction). Collectively, our results suggest that XZK effectively suppresses vulnerable plaque progression and rupture by mitigating macrophage ER stress and consequently inhibiting apoptosis and the NF-κB pro-inflammatory pathway, thereby providing an alternative therapeutic strategy for stabilizing atherosclerotic plaques.
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