Background: The transcription factor BACH1 (BTB and CNC homology 1) suppressed endothelial cells (ECs) proliferation and migration and impaired angiogenesis in the ischemic hindlimbs of adult mice. However, the role and underlying mechanisms of BACH1 in atherosclerosis remain unclear. Methods: Mouse models of atherosclerosis in endothelial cell (EC)-specific-Bach1 knockout mice were used to study the role of BACH1 in the regulation of atherogenesis and the underlying mechanisms. Results: Genetic analyses revealed that coronary artery disease-associated risk variant rs2832227 was associated with BACH1 gene expression in carotid plaques from patients. BACH1 was upregulated in ECs of human and mouse atherosclerotic plaques. Endothelial Bach1 deficiency decreased turbulent blood flow- or western diet-induced atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules (ICAM1 [intercellular cell adhesion molecule-1] and VCAM1 [vascular cell adhesion molecule-1]), and reduced plasma TNF-α (tumor necrosis factor-α) and IL-1β levels in atherosclerotic mice. BACH1 deletion or knockdown inhibited monocyte–endothelial adhesion and reduced oscillatory shear stress or TNF-α-mediated induction of endothelial adhesion molecules and/or proinflammatory cytokines in mouse ECs, human umbilical vein ECs, and human aortic ECs. Mechanistic studies showed that upon oscillatory shear stress or TNF-α stimulation, BACH1 and YAP (yes-associated protein) were induced and translocated into the nucleus in ECs. BACH1 upregulated YAP expression by binding to the YAP promoter. BACH1 formed a complex with YAP inducing the transcription of adhesion molecules. YAP overexpression in ECs counteracted the antiatherosclerotic effect mediated by Bach1-deletion in mice. Rosuvastatin inhibited BACH1 expression by upregulating microRNA let-7a in ECs, and decreased Bach1 expression in the vascular endothelium of hyperlipidemic mice. BACH1 was colocalized with YAP, and the expression of BACH1 was positively correlated with YAP and proinflammatory genes, as well as adhesion molecules in human atherosclerotic plaques. Conclusions: These data identify BACH1 as a mechanosensor of hemodynamic stress and reveal that the BACH1-YAP transcriptional network is essential to vascular inflammation and atherogenesis. BACH1 shows potential as a novel therapeutic target in atherosclerosis.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD⁺ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD⁺ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

Atherosclerosis (AS) is the leading cause of stroke and death worldwide. Although many lipid-lowering or antiplatelet medicines have been used to prevent the devastating outcomes caused by AS, the serious side effects of these medicines cannot be ignored. Moreover, these medicines are aimed at preventing end-point events rather than addressing the formation and progression of the lesion. Rapamycin (sirolimus), a fermentation product derived from soil samples, has immunosuppressive and anti-proliferation effects. It is an inhibitor of mammalian targets of rapamycin, thereby stimulating autophagy pathways. Several lines of evidence have demonstrated that rapamycin possess multiple protective effects against AS through various molecular mechanisms. Moreover, it has been used successfully as an anti-proliferation agent to prevent in-stent restenosis or vascular graft stenosis in patients with coronary artery disease. A thorough understanding of the biomedical regulatory mechanism of rapamycin in AS might reveal pathways for retarding AS. This review summarizes the current knowledge of biomedical mechanisms by which rapamycin retards AS through action on various cells (endothelial cells, macrophages, vascular smooth muscle cells, and T-cells) in early and advanced AS and describes clinical and potential clinical applications of the agent.

Purpose: To compare the characteristics and learning curve of the transfemoral approach (TFA) vs the transradial approach (TRA) for cerebral angiography. Materials and Methods: Between February 2016 and April 2017, 101 patients undergoing cerebral angiography were enrolled. Fifty-one patients (mean age 67 years; 40 men) were randomized to TFA and 50 (mean age 68 years; 41 men) to TRA using a computer-generated random table. The patients’ demographic and angiographic data were recorded and analyzed. The learning curve of a novice interventionist was analyzed for procedure time, puncture time, fluoroscopy time, and contrast volume as markers of technical proficiency with TFA compared with TRA. Median values are given with the interquartile range (IQR). Results: Procedure time [35 (IQR 30, 47.5) vs 31.0 (IQR 25.0, 48.9) minutes, p=0.16), fluoroscopy time [10.3 (IQR 7.6, 13.9) vs 9.4 (IQR 6.1, 17.6) minutes, p=0.70], contrast volume [105 (IQR 92, 120) vs 95.5 (IQR 90, 111.3) mL, p=0.13), radiation exposure [390.2 (IQR 268.2, 617.9) vs 455.8 (IQR 286.8, 602.3) mGy, p=0.74], and the number of catheter exchanges [1 (IQR 1, 3) vs 1 (IQR 1, 1), p=0.06] were not significantly different between the TFA and TRA groups, respectively, but puncture time was shorter with TFA than with TRA [0.6 (IQR 0.5, 1.1) vs 1 (IQR 0.6, 1.9) minutes, p=0.01]. The learning curve was steeper with TRA than with TFA in the beginning stages of training, but with increasing experience, the procedure and fluoroscopy times were better for TRA than for TFA. Training progress was made earlier in TRA. Conclusion: TRA is a reasonable alternative to TFA for cerebral angiography. TRA has a shorter learning curve for novice interventionists.

Aims: To investigate the differentially expressed genes (DEGs) and molecular interaction in unstable atherosclerotic carotid plaques. Methods: Gene expression datasets GSE41571, GSE118481, and E-MTAB-2055 were analyzed. Co-regulated DEGs in at least two datasets were analyzed with the enrichment of Gene Ontology Biological Process (GO-BP), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI) networks, interrelationships between miRNAs/transcriptional factors, and their target genes and drug–gene interactions. The expression of notable DEGs in human carotid artery plaques and plasma was further identified. Results: The GO-BP enrichment analysis revealed that genes associated with inflammatory response, and extracellular matrix organization were altered. The KEGG enrichment analysis revealed that upregulated DEGs were enriched in the tuberculous, lysosomal, and chemokine signaling pathways, whereas downregulated genes were enriched in the focal adhesion and PI3K/Akt signaling pathway. Collagen type I alpha 2 chain (COL1A2), adenylate cyclase 3 (ADCY3), C-X-C motif chemokine receptor 4 (CXCR4), and TYRO protein tyrosine kinase binding protein (TYROBP) might play crucial roles in the PPI networks. In drug–gene interactions, colonystimulating factor-1 receptor had the most drug interactions. Insulin-like growth factor binding protein 6 (IGFBP6) was markedly downregulated in unstable human carotid plaques and plasma. Under a receiver operating characteristic curve analysis, plasma IGFBP6 had a significant discriminatory power (AUC, 0.894; 95% CI, 0.810–0.977), with a cutoff value of 142.08 ng/mL. Conclusions: The genes COL1A2, ADCY3, CXCR4, and TYROBP are promising targets for the prevention of unstable carotid plaque formation. IGFBP6 may be an important biomarker for predicting vulnerable plaques.