Abstract:Metabolic reprogramming plays a crucial role in the pathogenesis of cardiovascular diseases (CVD). Lactate, a metabolite of glycolysis, is now considered an important cellular signaling molecule involved in regulating various metabolic processes within the microenvironment. Recently discovered lactylation modifications have been found to play significant roles in CVD such as atherosclerosis (As), vascular or valve calcification, myocardial infarction, heart failure (HF), and pulmonary hypertension (PH). This review summarizes the regulatory mechanisms of lactate and lactylation modifications in these CVD, aiming to provide new insights for their precise prevention and treatment strategies.

Abstract:Vascular remodeling refers to a series of structural and functional abnormalities in the vascular wall, which is characterized by stenosis of the lumen, thickening of the vascular wall, reduction of vascular elasticity and compliance caused by changes in the microenvironment inside and outside the blood vessel, and ultimately the occurrence of cardiovascular events. Although the prevention, diagnosis and intervention of clinical cardiovascular diseases have improved, vascular dysfunction caused by vascular remodeling is still a huge problem and challenge that plagues clinical efficacy. N6-methyladenosine (m⁶A) modification is the most common and abundant post-transcriptional modification type in eukaryotic RNA. m⁶A methyltransferase, m⁶A demethylase and m⁶A reading protein are responsible for the occurrence, deletion and recognition of m⁶A modification, respectively. The m⁶A modification regulates the fate of important transcripts by participating in the splicing, degradation, translation, and subcellular translocation of RNA target molecules, thereby playing a regulatory role in the maintenance of vascular physiological homeostasis and pathological remodeling. Studies have confirmed that m⁶A modification-mediated vascular endothelial cell (EC) dysfunction, phenotypic transformation,abnormal proliferation, migration of medial vascular smooth muscle cell (VSMC), and aggregation and activation of monocytes/macrophages are involved in the occurrence and development of vascular remodeling diseases such as atherosclerosis and aneurysms. This article reviews the recent literatures on m⁶A modification in vascular remodeling, and discusses the effect of m⁶A methylation modification of important target molecules related to vascular remodeling on vascular cells function. Based on these, the intervention of m⁶A methylation may be a new target for clinical treatment and diagnosis in the future.

Abstract:Aim To investigate whether protein inhibitor of activated STAT3 (PIAS3) deficiency exacerbates the occurrence and development of atherosclerosis (As) in female ApoE knockout mice. Methods PIAS3 gene knockout mice with ApoE－/－ background (PIAS3－/－/ApoE－/－) and their littermate PIAS3＋/＋/ApoE－/－ mice were bred and fed with a high-fat/high-cholesterol diet for 12 weeks to induce As. Body weight (every week) and plasma lipid levels including total cholesterol, triglyceride, high density lipoprotein cholesterol and non-high density lipoprotein cholesterol (every 4 weeks) of the mice were measured. Oil red O staining, HE staining, immunohistochemistry staining and immunofluorescence staining were performed on mouse aortic tree and frozen sections of aortic root to evaluate the area, cellular composition and stability of As plaques. Moreover, the expression of estrogen receptor α (ERα) and its co-localization with vascular smooth muscle cells (VSMC) in plaques were determined by immunofluorescence staining. Results Compared with PIAS3＋/＋/ApoE－/－ mice, PIAS3－/－/ApoE－/－ mice showed no significant differences in body weight, major organ weight (heart, liver, spleen, kidney and epididymal fat) and plasma lipid levels; however, PIAS3 deficiency promoted the formation of As in female PIAS3－/－/ApoE－/－ mice. Compared with PIAS3＋/＋/ApoE－/－ mice, PIAS3－/－/ApoE －/－ mice showed an increased lipid accumulation and a decreased VSMC content in As plaques (P＜0.05), leading to a decrease in plaque stability. In addition, the expression of ERα in the As plaques of PIAS3－/－/ApoE－/－ mice was significantly downregulated (P＜0.05), and there was a obvious co-localization between ERα and VSMC. The reduction of VSMC content in PIAS3－/－/ApoE－/－ mouse plaques might lead to a decrease of ERα expression, thereby weakening the anti-As effect of estrogen. Conclusion PIAS3 deficiency exacerbates the formation of As plaques in female PIAS3－/－/ApoE－/－ mice, which might be due to the regulatory effect of PIAS3 on ERα expression in plaques.

Abstract:Aim To investigate the effect and potential mechanisms of tetramethylpyrazine (TMP) on atherosclerotic plaques. Methods 43 ApoE－/－ mice were used to establish the animal model of atherosclerosis (As) by high-fat diet for 8 weeks, 3 of which were used for model outcome verification, and another 40 model mice were randomly divided into model group, TMP low dose (25 mg/kg) group, TMP medium dose (50 mg/kg) group, TMP high dose (100 mg/kg) group and atorvastatin (AT, 2.6 mg/kg) group, with 8 mice in each group; another 8 C57BL/6J mice were set as control group. After gavaging administration for 8 weeks, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL) in the serum were detected by biochemical methods, and the As index was calculated. The levels of oxidized low density lipoprotein (ox-LDL), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) in serum were detected by ELISA method. The pathological changes of aorta was evaluated by HE staining. The aortic plaque formation was evaluated by oil red O staining, and the plaque area percentage was calculated. The aortic fibrosis was evaluated by Masson staining, and the collagen area percentage was calculated. The expression of monocyte macrophage antibody-2 (MOMA-2) and α-smooth muscle actin (α-SMA) in the aorta was detected by immunohistochemistry (IHC) method, and the plaque vulnerability index was calculated. The mRNA and protein expression of peroxisome proliferator-activated receptor γ (PPARγ), nuclear factor-κB p65 (NF-κB p65) in aorta were detected by RT-qPCR or Western blot method. Results Compared with control group, the levels of TC, TG, LDL, ox-LDL, TNF-α, IL-1β, MCP-1, ICAM-1 in serum and As index of the mice were significantly increased in model group, while the level of HDL was significantly decreased (P＜0.05). The aorta showed pathological changes such as uneven thickening of the intima, accumulation of foam cells and fat cells, formation of a large number of plaques, lumen stenosis and infiltration of inflammatory cells; the percentage of aortic plaque area, percentage of collagen area, MOMA-2 and α-SMA positive area, plaque vulnerability index were all significantly increased (P＜0.05). The mRNA and protein expression of PPARγ in aorta were significantly decreased, and the mRNA and protein expression of NF-κB p65 were significantly increased (P＜0.05). Compared with model group, the levels of TC, TG, LDL, ox-LDL, TNF-α, IL-1β, MCP-1, ICAM-1 in serum and As index of the mice were significantly decreased in the TMP medium, high dose group and AT group, the level of HDL was significantly increased (P＜0.05). The pathological changes of aorta were significantly improved. The plaque area percentage, collagen area percentage, MOMA-2 positive area percentage and plaque vulnerability index were significantly decreased, and the α-SMA positive area percentage was significantly increased (P＜0.05). The mRNA and protein expression of PPARγ in aorta were significantly increased, the mRNA and protein expression of NF-κB p65 were significantly decreased (P＜0.05). Moreover, TMP exhibited a certain dose-dependent effect on various detection indicators (except MCP-1) in As mice. The regulatory effect of TMP high dose group on various detection indicators (except LDL and As index) in As mice was comparable or superior to those of AT group. Conclusion TMP can reduce the area of As plaque and improve the stability of vulnerable plaque in As mice, its mechanism may be related to regulating PPARγ/NF-κB signaling pathway, improving lipid metabolism and inhibiting inflammatory response.

Abstract:Aim To clarify the role of sirtuin 1(SIRT1)/dynamin-related protein 1(DRP1) in genistein inhibiting oxidized low density lipoprotein(ox-LDL)-induced apoptosis of human umbilical vein endothelial cells(HUVEC). Methods HUVECs were cultured in vitro. The levels of mitochondrial fission factor (MFF), mitochondrial fission protein 1 (FIS1), mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), Bcl-2, Bax, cytochrome c (Cyt c), apoptotic protease activating factor 1 (APAF1), cleaved Caspase-9, cleaved Caspase-3, p-DRP1(Ser616) and acetylation-DRP1 (ac-DRP1), as well as the interaction between p-DRP1 and Bax were examined. Results Compared with ox-LDL treatment, genistein pretreatment suppressed the activity of DRP1 through diminishing acetylation and phosphorylation, which was associated with activating SIRT1(all P＜0.05). Genistein pretreatment inhibited mitochondrial fission by enhancing MFN1, MFN2 and OPA1, and reducing MFF and FIS1(all P＜0.05). Genistein pretreatment suppressed apoptosis through inhibiting the interaction between p-DRP1 and Bax, accompanied with increasing Bcl-2 and decreasing Bax, Cyt c, APAF1, cleaved Caspase-9 and Caspase-3 (all P＜0.05). Conclusion Genistein suppressed ox-LDL-induced mitochondrial fission and apoptosis through activating SIRT1and inhibiting DRP1 in HUVEC.Therefore, SIRT1/DRP1 had a crucial role in genistein inhibiting ox-LDL-induced apoptosis in HUVEC.

Abstract:Aim To explore the relationship between multiple cardiovascular and metabolic diseases and falls in middle-aged and elderly people. Methods Using the fifth dataset of the China Health and Retirement Longitudinal Study (CHARLS), 18 968 middle-aged and elderly people aged 45 years and above were enrolled as study subjects. The relationship between multiple cardiovascular and metabolic diseases and falls was analyzed by Logistic regression model. Results The incidence rates of falls, severe falls and hip fractures in the study subjects were 17.3%, 6.8% and 0.9%, respectively. Cardiovascular and metabolic diseases were positively associated with the risk of falls. Compared with study subjects without cardiovascular and metabolic diseases, those with 1,2, 3 and 4 cardiovascular and metabolic diseases had a 13%, 44%, 69% and 91% increased risk of falls, respectively, with OR (95%CI) of 1.13 (1.02～1.25), 1.44 (1.29～1.61), 1.69 (1.48～1.93) and 1.91 (1.56～2.32); the risk of serious falls increased by 22%, 51%, 69% and 102%, respectively, with OR (95%CI) of 1.22 (1.05～1.42), 1.51 (1.27～1.78), 1.69 (1.38～2.05) and 2.02 (1.54～2.66). The risk of hip fractures increased by 95%, 147% and 157% in study subjects with 2,3 and 4 cardiovascular and metabolic diseases, respectively, with OR (95%CI) of 1.95 (1.24～3.05), 2.47 (1.50～4.07) and 2.57 (1.26～5.20). Conclusion Multiple cardiovascular and metabolic diseases significantly increased the risk of falls in middle-aged and elderly people.

Abstract:Aim To investigate the correlation between serum solube growth stimulation expressed gene 2 protein (sST2) and early reperfusion arrhythmia (ERA) after emergency percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods A total of 202 STEMI patients who underwent emergency PCI from November 2020 to August 2022 in the Cardiac Center of Liaoning Provincial People's Hospital were divided into two groups based on the occurrence of ERA within 48 hours after PCI:ERA group and non-ERA group.Serum sST2 level and clinical data were compared between the groups. Univariable and multivariable Logistic regression analysis were used to explore the association between serum sST2 level and ERA occurrence, and restricted cubic spline model was applied to identify independent risk factors for ERA. Results There were 83 (41.1%) patients experienced ERA within 48 hours after PCI. Compared with the non-ERA group, the patients in ERA group had shorter time from chest pain to reperfusion and higher serum sST2 level (P＜0.001). Multivariate Logistic regression analysis showed that for STEMI patients, elevated serum sST2 level (sST2≥45.03 μg/L), early reperfusion time (chest pain to successful reperfusion time≤5.23 h), high thrombosis burden, and right coronary artery as the infarct related artery (IRA) were independent risk factors for ERA after emergency PCI. The restricted cubic spline model suggested that the serum sST2 level of STEMI patients was nonlinearly correlated with the risk of ERA after PCI (P＜0.01), and the cutoff point was 45.12 μg/L. ROC curve analysis showed that the area under the ROC curve of serum sST2 level in predicting ERA occurrence after PCI was 0.827 (95%CI:0.771~0.883). Conclusion The high serum sST2 level before PCI is an independent risk factor for ERA occurrence after PCI in patients with STEMI. When serum sST2 ＞45.12 μg/L, its level is positively correlated with the risk of ERA.

Abstract:Aim To explore the relationship between serum uric acid (UA)/creatinine (Cr), homocysteine (Hcy), apolipoprotein A1 (ApoAl) levels and plaque stability in patients with carotid atherosclerosis (CAS) and the predictive value for secondary acute cerebral infarction (ACI). Methods 138 patients with CAS were selected as the research subjects and further divided into stable plaque group and unstable plaque group based on the stability of plaques. Heathy individuals undergoing physical examinations were selected as the control group. Enzyme cycling method was used to detect Hcy level, latex enhanced immunoturbidimetry method was used to detect ApoA1 level, uricase method was used to detect UA level, enzyme method was used to detect Cr level, and UA/Cr ratio was calculated. Baseline data and laboratory indicators in the no plaque group, stable plaque group and unstable plaque group were compared. The relationship between laboratory indicators and intima-media thickness (IMT) was analyzed using Spearman correlation analysis. Cox regression model was used for univariate and multivariate analysis of secondary ACI in patients with CAS, and ROC curve was used to evaluate the predictive value of serum UA/Cr, Hcy and ApoA1 levels for it. Results Among 138 patients with CAS, there were 74 cases in the stable plaque group and 64 cases in the unstable plaque group; there were 46 cases of secondary ACI. There were 42 cases in the control group. Compared with the control group, the stable plaque group and unstable plaque group had lower levels of serum ApoA1 and high density lipoprotein cholesterol (HDLC), and higher levels of serum UA/Cr, Hcy, low density lipoprotein cholesterol (LDLC) and IMT (P＜0.05). Spearman correlation analysis showed that IMT in the plaque group was positively correlated with serum UA/Cr and Hcy levels (r＝0.535 and r＝0.681, P＜0.05), and negatively correlated with ApoA1 levels (r＝－0.594, P＜0.05). Cox regression analysis showed that unstable plaques, high serum UA/Cr and Hcy levels were risk factors for secondary ACI, while high serum ApoA1 levels were protective factors for secondary ACI (P＜0.05). ROC curve analysis showed that the sensitivity and specificity of combining serum UA/Cr, Hcy and ApoA1 for predicting secondary ACI in the CAS patients were 85.45% and 82.67%, respectively, with an AUC of 0.920, which was higher than the individual diagnosis of UA/Cr, Hcy and ApoA1. Conclusions The levels of serum UA/Cr and Hcy are significantly positively correlated with plaque formation and stability in the CAS patients, while ApoA1 is significantly negatively correlated with them. These three factors are independent influencing factors for secondary ACI in the CAS patients, and their combined prediction of ACI has a higher efficacy.

Abstract:Angiogenesis is a key link in the development of atherosclerotic plaques. Inhibiting angiogenesis contributes to plaque stabilization and reduces the risk of related cardiovascular events. Apolipoprotein A1 binding protein (A1BP), an important secretory protein, has been shown in a growing body of research to play a significant role in the regulation of angiogenesis. This article aims to elucidate the mechanisms of action of A1BP on angiogenesis and cardiovascular diseases, thereby providing new perspectives for the clinical treatment of cardiovascular diseases.

Abstract:Atherosclerosis is a chronic vascular wall disease. The clinical manifestations are abnormal lipid deposition, fibrous hyperplasia, calcium deposition, etc. under the intima of the affected artery lesions. Its initial link is related to endothelial cell dysfunction, which can be triggered and aggravated by different risk factors of atherosclerosis, including oxidative stress, hemodynamic abnormalities, endothelial cell senescence and inflammation, etc. Exploring the mechanism of endothelial cell dysfunction is conducive to the discovery of potential treatments for atherosclerosis. This article summarizes the mechanism and research progress of drug therapy for endothelial cell dysfunction in atherosclerosis.

Abstract:With the widespread application of drug-eluting stent (DES) technology and rapid advancement in stent bioengineering, the efficacy and safety of percutaneous coronary intervention (PCI) have significantly improved. However, the incidence of in-stent restenosis (ISR) remains a critical issue, with approximately 1% to 2% of patients requiring repeat revascularization annually. Given the global implantation of millions of DES each year, ISR has emerged as a major clinical challenge demanding urgent resolution. The pathological mechanisms underlying DES-ISR are complex and heterogeneous, and with continuous progress in intracoronary imaging techniques, these mechanisms and classifications have been further elucidated. Concurrently, therapeutic tools and strategies for ISR are undergoing ongoing development and optimization. This review summarizes recent research progress and achievements in the definition, classification, pathological mechanisms, imaging characteristics, and treatment approaches related to DES-ISR.