Prevention of neointima formation is the key to improving long-term outcomes after stenting or coronary artery bypass grafting. RNA N 6 -methyladenosine (m 6 A) methylation has been reported to be involved in the development of various cardiovascular diseases, but whether it has a regulatory effect on neointima formation is unknown.Herein, we revealed that methyltransferase-like 3 (METTL3), the major methyltrans-
Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.
Background Aberrant proliferation of vascular smooth muscle cells (VSMCs) is the cause of neointima formation followed by vascular injury. Autophagy is involved in this pathological process, but its function is controversial. Recently, we found that methyltransferase like 3 (METTL3) inhibited VSMC proliferation by activating autophagosome formation. Moreover, we also demonstrated that METTL3 reduced the levels of phosphorylated mammalian target of rapamycin (p-mTOR) and cyclin dependent kinase 1 (p-CDK1/CDC2), which were critical for autophagy and proliferation regulation. However, whether mTOR and CDK1 mediated the function of METTL3 on autophagy and proliferation in VSMCs remains unknown. Results We showed that the activator of mTOR, MHY1485 largely reversed the effects of METTL3 overexpression on VSMC autophagy and proliferation. Rapamycin, the inhibitor of mTOR, obviously nullified the pro-proliferation effects of METTL3 knockdown by activating autophagy in VSMCs. Unexpectedly, mTOR did not contribute to the impacts of METTL3 on migration and phenotypic switching of VSMCs. On the other hand, by knockdown of CDK1 in VSMC with METTL3 deficiency, we demonstrated that CDK1 was involved in METTL3-regulated proliferation of VSMCs, but this effect was not mediated by autophagy. Conclusions We concluded that mTOR but not CDK1 mediated the role of METTL3 on VSMC proliferation and autophagy.
IntroductionThe pathophysiology of coronary chronic total occlusion (CTO) has not been fully elucidated.MethodsIn the present study, we aimed to investigate the potential plasma biomarkers associated with the pathophysiologic progression of CTO and identify protein dynamics in the plasma of CTO vessels immediately after successful revascularization. We quantitatively analyzed the plasma proteome profiles of controls (CON, n = 10) and patients with CTO pre- and post- percutaneous coronary intervention (PCI) (CTO, n = 10) by data-independent acquisition proteomics. We performed enzyme-linked immunosorbent assay (ELISA) to further confirm the common DEPs in the two-group comparisons (CON vs. CTO and CTO vs. CTO-PCI).ResultsA total of 1936 proteins with 69 differentially expressed proteins (DEPs) were detected in the plasma of patients with CTO through quantitative proteomics analysis. For all these DEPs, gene ontology (GO) analysis and protein-protein interaction (PPI) analysis were performed. The results showed that most of the proteins were related to the negative regulation of proteolysis, regulation of peptidase activity, negative regulation of hydrolase activity, humoral immune response, and lipid location. Furthermore, we identified 1927 proteins with 43 DEPs in the plasma of patients with CTO vessels after immediately successful revascularization compared to pre-PCI. GO analysis revealed that the above DEPs were enriched in the biological processes of extracellular structure organization, protein activation cascade, negative regulation of response to external stimulus, plasminogen activation, and fibrinolysis. More importantly, we generated a Venn diagram to identify the common DEPs in the two-group comparisons. Seven proteins, ADH4, CSF1, galectin, LPL, IGF2, IgH, and LGALS1, were found to be dynamically altered in plasma during the pathophysiological progression of CTO vessels and following successful revascularization, moreover, CSF1 and LGALS1 were validated via ELISA.ConclusionsThe results of this study reveal a dynamic pattern of the molecular response after CTO vessel immediate reperfusion, and identified seven proteins which would be the potential targets for novel therapeutic strategies to prevent coronary CTO.
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