Abstract:Connexin 43 (Cx43) serves as the fundamental component of gap junctions in cardiomyocytes, facilitating intercellular electrical signal transmission and metabolic coupling. It plays a crucial role in maintaining cardiac electrophysiological stability. The expression, subcellular localization, and functional state of Cx43 are regulated by a variety of post-translational modifications, such as phosphorylation, glycosylation, acetylation, ubiquitination, and S-nitrosylation.During myocardial ischemia-reperfusion injury, Cx43 undergoes dephosphorylation during the ischemic phase, leading to gap junction uncoupling. Upon reperfusion, oxidative stress accelerates Cx43 degradation and induces abnormal opening of hemichannels, thereby exacerbating ion imbalance, calcium overload, and oxidative damage, which ultimately contribute to arrhythmias and cardiomyocyte apoptosis. Moreover, Cx43 exhibits cardioprotective potential under specific subcellular localization (e.g., in mitochondria) and particular modification states. This review systematically summarizes the biological characteristics and post-translational modifications of Cx43, and evaluates its multifaceted mechanisms in myocardial ischemia-reperfusion injury through the regulation of electro-metabolic coupling, as well as its potential as a therapeutic target.

Abstract:Aim To investigate the relaxation effect of farrerol on isolated mouse pulmonary artery (PA) rings pre-contracted with different vasoconstrictors, and to determine whether this effect is related to the Kv7 channels. Methods The vascular tension was measured in pulmonary artery rings using wire myography. Firstly, the vasodilatory effects of farrerol at concentrations of 10－6,3×10－6,0－5,3×10－5 and 10－4 mol/L were examined after pre-contraction of pulmonary arteries with 10－8 mol/L norepinephrine (NE) or 10－7 mol/L 5-hydroxytryptamine (5-HT). The influence of the presence or absence of PA endothelium on farrerol-induced relaxation of PA rings was observed. The inhibitory effect of pre-incubation with farrerol (RC₅₀, 60 min) on the graded contraction of PA induced by NE (10－10～10－7 mol/L) and 5-HT (10－8～10－5 mol/L) was measured. The effect of farrerol on intracellular calcium concentration ([Ca²＋]_in) in acute isolated mouse pulmonary arterial smooth muscle cell (PASMC) was detected using the Fluo 4-AM fluorescent calcium probe. Finally, the effect of the Kv7 channels blocker XE991 (1 μmol/L, 15 min incubation) on farrerol-induced graded relaxation of pulmonary arteries was observed. Results Farrerol (10－6～10－4 mol/L) significantly relaxed PA rings pre-contracted with NE or 5-HT (P＜0.01), and this relaxing effect was endothelium-independent. Pre-incubation with farrerol at concentration of RC₅₀ for 60 min markedly attenuated the maximal contractions induced by both NE (10－10～10－7 mol/L) and 5-HT (10－8～10－5 mol/L). Furthermore, in PASMC loaded with Fluo 4-AM, farrerol (RC₅₀) significantly inhibited the 30 mmol/L KCl-induced elevation of [Ca²＋]_in (P＜0.01). Pre-treatment with the blocker XE991 (1 μmol/L 15 min) significantly attenuated farrerol-induced relaxation (P＜0.01). Conclusion Farrerol relaxes isolated mouse PA by activating Kv7 channels.

Abstract:Aim To investigate the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the apoptosis of human umbilical vein endothelial cells induced by nitrated low density lipoprotein (N-LDL) and its molecular mechanism. Methods Differential expression analysis was performed using publicly available transcriptome datasets to assess the correlation between N-LDL and PCSK9 expression in relevant diseases. Human umbilical vein endothelial cells were treated with N-LDL to induce apoptosis, which was detected by Hoechst33342/propidium iodide (PI) staining. Expression of apoptosis-related molecules was assessed by Western blot. Reactive oxygen species (ROS) production and mitochondrial membrane potential were measured using dihydroethidium (DHE) and JC-1 probes, respectively. Lipid accumulation in human umbilical vein endothelial cells was evaluated by oil red O staining. PCSK9 knockdown was achieved using siRNA. Results Following N-LDL treatment of human umbilical vein endothelial cells, CCK-8 assay results demonstrated a significant decrease in cell viability compared with both the control and LDL groups (P＜0.01). Western blot analysis showed markedly increased expression of the pro-apoptotic proteins Caspase-9, Caspase-3 and Bax, accompanied by a significant reduction in the anti-apoptotic protein Bcl-2 (P＜0.01). Hoechst33342/PI double staining revealed an increased number of positive cells, indicating the occurrence of apoptosis. N-LDL upregulated the protein expression of the key cholesterol metabolism transcription factor sterol regulatory element-binding protein 2 (SREBP2) and its downstream target protein PCSK9 in a concentration-dependent manner (P＜0.05), with a consistent trend of both. Oil red O staining demonstrated that N-LDL treatment promoted intracellular lipid accumulation. Moreover, flow cytometry and fluorescence analyses showed that N-LDL increased intracellular reactive oxygen species (ROS) production and significantly reduced mitochondrial membrane potential (P＜0.05), indicating mitochondrial dysfunction. Notably, silencing PCSK9 significantly reversed these N-LDL-induced mitochondrial dysfunction and apoptotic alterations in human umbilical vein endothelial cells, as evidenced by reduced ROS production, restoration of mitochondrial membrane potential, decreased expression of Caspase-9 , Caspase-3 and Bax, upregulated Bcl-2 expression, and a decreased number of PI-positive cells (P＜0.05). Conclusion N-LDL upregulates SREBP2 expression, promotes the expression of PCSK9, thereby activating the mitochondrial apoptosis pathway, and ultmately inducing apoptosis in human umbilical vein endothelial cells.

Abstract:Aim To investigate the predictive factors for microvascular obstruction (MVO) in patients with acute ST-segment elevation myocardial infarction (STEMI) and its impact on patient prognosis using cardiac magnetic resonance (CMR). Methods A total of 102 patients with acute STEMI who underwent primary percutaneous coronary intervention (PCI) in the Department of Cardiology from September 2023 to June 2025 were prospectively enrolled. CMR was performed on the patients at one week and six months after the operation, respectively. The patients were divided into MVO group (n＝48) and non-MVO group (n＝54) based on the presence or absence of MVO signs on CMR. Differences in clinical characteristics between the two groups were analyzed, and univariate and multivariate Logistic regression analysis were performed to identify independent risk factors of MVO. ROC curves were used to assess the predictive value of risk factors for MVO, and CMR follow-up examinations were conducted to evaluate the impact of MVO on left ventricular remodeling. Results Compared with the non-MVO group, the MVO group had significantly higher admission heart rate, platelet-to-lymphocyte ratio (PLR), creatine kinase-MB (CK-MB), and triglyceride-glucose index (TyG), as well as higher proportion of anterior wall infarction (P＜0.05). Multivariate Logistic regression analysis showed that increased TyG (OR＝6.4,5%CI:1.547～25.854, P＝0.01), elevated PLR (OR＝1.7,5%CI:1.018～1.056, P＜0.001), higher admission heart rate (OR＝1.7,5%CI:1.07～1.208, P＜0.001), and elevated peak level of CK-MB (OR＝1.1,5%CI:1.004～1.016, P＝0.001) were independent risk factors for the occurrence of MVO in patients with acute STEMI after primary PCI. The results of ROC curve showed that admission heart rate (sensitivity:0.521, specificity:0.907, AUC＝0.76), TyG (sensitivity:0.875, specificity:0.519, AUC＝0.666), PLR (sensitivity:0.896, specificity:0.426, AUC＝0.688), CK-MB peak (sensitivity:0.854, specificity:0.704, AUC＝0.791) had limited predictive value for MVO. However, their combined prediction model (sensitivity:0.833, specificity:0.852, AUC＝0.901) significantly improved the ability to predict the occurrence of MVO; after 6 months of follow-up observation, the incidence of left ventricular malignant remodeling in the MVO group was significantly higher than in the non-MVO group (42.2% vs. 20.4%, P＝0.022), and the corresponding left ventricular end-systolic volume index (LVESVI) and left ventricular end-diastolic volume index (LVEDVI) at 6 months were significantly higher in the MVO group than in the non-MVO group (LVESVI:51(39~59) mL/m² vs. 37(30~45) mL/m², P＜0.001; LVEDVI: 81(72~100)mL/m² vs. 70(57~85)mL/m², P＜0.001). Conclusion Based on CMR parameters in acute STEMI patients, this study identified increased TyG, elevated PLR, higher CK-MB peak level, and accelerated admission heart rate as independent risk factors for MVO; Moreover, their combined predictive value was higher, and patients with MVO signs had a significantly increased risk of developing left ventricular malignant remodeling.

Abstract:Aim To compare tissue motion mitral annular displacement (TMAD) and volumetric indices in patients with acute myocardial infarction (AMI) under different volume load conditions, and to analyze their correlation and predictive value for patient prognosis. Methods The clinical data of 164 patients with AMI were collected, and they were divided into volume overload group (n＝98) and non-volume overload group (n＝66) according to the relative volume balance level of patients. All patients were followed up for 30 days, and further classified into poor prognosis group (n＝70) and good prognosis group (n＝94) based on the occurrence of death or rehospitalization. The general data, TMAD parameters and volumetric indexes were compared between groups. The Pearson correlation analysis was used to assess the correlation between TMAD parameters and volumetric indexes. Multivariate Logistic regression analysis was performed to analyze the influencing factors of poor prognosis of AMI patients. A generalized linear model was employed to evaluate the effect of volume load on the regression relationship between TMAD parameters and prognosis. ROC curves were used to assess the efficacy of TMAD parameters and volumetric indexes in predicting poor prognosis in patients with AMI. Results Compared with the non-volume overload group, patients in the volume overload group had lower systolic blood pressure (SBP), diastolic blood pressure (DBP), TMAD parameters, albumin (ALB), hemoglobin (Hb), and hematocrit (HCT) levels, while their sequential organ failure assessment (SOFA) scores, simplified acute physiology score Ⅱ (SAPS Ⅱ) scores, creatinine, blood urea nitrogen (BUN), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) were higher (P＜0.05). Correlation analysis showed that the maximal displacement of the annulus at the interventricular septum (TMAD1), the maximal displacement of the annulus at the left ventricular lateral wall (TMAD2), and the maximal displacement at the midpoint of the mitral annulus between the interventricular septum and lateral wall (TMADMidpt) and its percentage of left ventricular long axis (TMADMidpt%) were all significantly positively correlated with ALB, Hb and HCT, and significantly negatively correlated with PCWP and CVP (all P＜0.001). Compared with the good prognosis group, the poor prognosis group had a higher proportion of volume overload, lower TMAD1, TMAD2, TMADMidpt and HCT levels, and higher PCWP and CVP levels (all P＜0.05). Increases in TMAD1, TMAD2, TMADMidpt and HCT were independent protective factors affecting patient prognosis, whereas increased volume load, PCWP and CVP were independent risk factors affecting patient prognosis (all P＜0.05). Results from the generalized linear model showed that as TMAD parameters increased, the negative correlation between volume load and poor prognosis gradually strengthened. ROC curve analysis showed that the combined detection of TMAD parameters (including TMAD1, TMAD2, TMADMidpt) and volume-related indicators (including HCT, PCWP, CVP) had an AUC of 0.971 (95%CI:0.952～0.986, P＜0.001), which was higher than for any individual indicator (TMAD1, TMAD2, TMADMidpt, HCT, PCWP, CVP), for the combined TMAD parameters (TMAD1, TMAD2, TMADMidpt), and for the combined volume-related indicators (HCT, PCWP, CVP). Conclusion TMAD can be used as an effective indicator to evaluate the volume load and prognosis of patients with AMI, combination detection with volumetric indexes can further improve the accuracy of prognosis prediction.

Abstract:Aim To quantitatively evaluate carotid artery stiffness in patients with type 2 diabetes mellitus (T2DM) complicated by hyperlipidemia using shear wave elastography (SWE). Methods 112 T2DM patients were included in this study. They were divided into simple diabetes group (n＝52) and hyperlipidemia group (n＝60) according to whether they were combined with hyperlipidemia. At the same time, healthy people were selected as the control group (n＝55). General data and biochemical indices were collected for each group. Conventional ultrasound was used to measure the intima-media thickness (IMT), peak systolic velocity (PSV), systolic diameter (Ds) and diastolic diameter (Dd) of the left common carotid artery, and the wall motion amplitude (ΔD) and stiffness coefficient (β) were calculated. SWE was applied to measure the mean of the maximum modulus (ME_max), the mean of mean elastic modulus (ME_mean) and the mean of minimum modulus (ME_min) of the left common carotid artery. Results The levels of fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDLC) in the simple diabetes group and the hyperlipidemia group were significantly higher than those in the control group, while the levels of high density lipoprotein cholesterol (HDLC) were significantly lower than those in the control group (all P＜0.05); The levels of TC, TG and LDLC in the hyperlipidemia group were significantly higher than those in the simple diabetes group, and the HDLC levels were significantly lower than those in the simple diabetes group (all P＜0.05). SWE parameters (ME_max, ME_mean and ME_min) in the simple diabetes group and the hyperlipidemia group were significantly higher than those in the control group (all P＜0.05), and SWE parameters in the hyperlipidemia group were significantly higher than those in the simple diabetes group (all P＜0.05). Pearson correlation analysis showed that IMT, TC, TG, LDLC, FBG and HbA1c were positively correlated with SWE parameters (all P＜0.05), while HDLC was negatively correlated with SWE parameters (all P＜0.05). Multivariable linear regression analysis indicated that T2DM and hyperlipidemia were independent risk factors for carotid SWE parameters (both P＜0.05). ConclusionHyperlipidemia is significantly correlated with deterioration of carotid elasticity in T2DM patients, and SWE technology can quantitatively evaluate carotid elasticity in T2DM patients complicated with hyperlipidemia.

Abstract:Aim To investigate the association between heart rate variability (HRV) and the risk of major adverse cardiovascular events (MACE) in elderly female with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM), and to evaluate the clinical value of HRV for prognostic stratification in this population. Methods A retrospective cohort study was conducted. A total of 103 elderly female patients with HFpEF complicated by T2DM who were hospitalized in the Affiliated Hospital of Qingdao University from September 1,9 to September 1,2 were enrolled. Baseline clinical data were collected at initial assessment, including demographic characteristics, laboratory results, echocardiographic parameters, and 24-hour Holter-derived HRV indices. Patients were followed for 1 year and divided into the observation group(MACE group) and the control group(non-MACE group) according to the occurrence of MACE. Baseline characteristics were compared between the two groups. Variables with P＜0.1 in univariable analysis were entered into least absolute shrinkage and selection operator (LASSO) regression for feature selection, followed by multivariable Cox proportional hazards regression to identify independent factors associated with MACE. Kaplan-Meier curves were constructed to estimate event-free survival, and between-group differences were evaluated using the Log-rank test. Results Compared with the control group, patients were older and had a higher prevalence of prior atrial fibrillation in the observation group (P＜0.05). The levels of N-terminal pro-B-type natriuretic peptide(NT-proBNP), the ratio of peak early diastolic mitral inflow velocity to early diastolic mitral annular velocity(E/e′), and left atrial volume index (LAVI) were higher in the observation group(all P＜0.05), whereas multiple HRV indices including standard deviation of all normal-to-normal R-R intervals (SDNN), root mean square of successive differences between normal-to-normal R-R intervals (RMSSD), percentage of successive normal-to-normal R-R intervals differing by more than 50 ms (pNN50), high-frequency power (HF), low-frequency power (LF), and very low-frequency power (VLF) were significantly lower (all P＜0.05). In addition, the use of β-blockers and dapagliflozin was less frequent in the observation group (P＜0.05). LASSO-Cox regression analysis showed higher NT-proBNP (HR＝1.1,5%CI:1.00～1.01) and LAVI (HR＝1.6,5%CI:1.04～1.30), as well as lower SDNN (HR＝0.4,5%CI:0.91～0.98), were independently associated with an increased risk of MACE, whereas dapagliflozin use was an independent protective factor (HR＝0.8,5%CI:0.07～0.45) (all P＜0.05). The patients were divided into low-HRV and high-HRV groups according to the median SDNN (82 ms). Kaplan-Meier survival analysis showed that the difference in MACE-free survival rates between the two groups was statistically significant (P＝0.0043). Conclusion Reduced HRV, especially SDNN, was significantly associated with an increased risk of MACE in elderly female patients with HFpEF and T2DM, suggesting that HRV may serve as a valuable indicator for evaluating autonomic dysfunction and adverse cardiovascular prognosis in this population.

Abstract:Matrine (MAT) is a natural alkaloid extracted from the traditional Chinese herb Sophora flavescens, combining the natural attributes of herbal medicine with the well-defined efficacy advantages of chemical drugs. It exerts broad regulatory effects in areas such as anti-inflammation, endothelial cell (EC) function protection, and phenotypic switching of vascular smooth muscle cells (VSMC). In recent years, MAT has attracted extensive attention in the field of vascular remodeling due to its multi-targeted regulatory properties. Research indicates that MAT participates in the onset and progression of various vascular remodeling-related diseases, including atherosclerosis (As), angiogenesis, and pulmonary hypertension (PH). Its mechanisms involve improving vascular endothelial cell (EC) dysfunction, regulating the phenotypic switching of VSMC, and inhibiting the abnormal activation and chemotaxis of monocytes/macrophages. This article systematically reviews the mechanisms of MAT in vascular remodeling. Based on this evidence, the application of MAT holds promise as a new direction for future clinical therapies.

Abstract:Vascular aging is an independent risk factor for cardio-cerebrovascular diseases. DNA methylation, as an important epigenetic regulatory mechanism, participates in the process of vascular aging through multiple pathways. First, DNA methylation can regulate the oxidative stress response, leading to excessive generation of reactive oxygen species (ROS), which damages vascular endothelial cells. Second, it can also induce inflammatory responses, promote the release of inflammatory factors, and disrupt vascular homeostasis. Furthermore, DNA methylation can affect telomere and mitochondrial function by interfering with telomerase activity and mitochondrial energy metabolism, thereby accelerating the aging process of vascular cells. These pathophysiological mechanisms interact and synergize in vivo, collectively promoting vascular aging and contributing to the development of various cardiovascular events, such as coronary heart disease, hypertension, and ischemic stroke. Therefore, DNA methylation plays an important role in promoting vascular aging and represents a key target for the prevention and treatment of aging-related cardio-cerebrovascular diseases.

Abstract:Calcification refers to the pathological process of abnormal deposition of calcium salts in body tissues, which includes two main categories:physiological calcification and ectopic calcification. The former is a normal physiological phenomenon, commonly observed in the development and maturation of teeth and bones; the latter, however, is a pathological condition where calcium salts deposit in non-osseous tissues, most typically affecting blood vessels and the myocardium. Clinical studies have shown that vascular calcification (VC) is closely related to osteoporosis (OP), and this mutually influential pathological phenomenon is referred to as the “calcification paradox”. Currently, the mechanisms underlying their coexistence have not been fully elucidated, but it is well-established that multiple common influencing factors exist, including disorders of calcium and phosphorus metabolism, chronic inflammatory responses, hormonal imbalances, and gut microbiota dysbiosis. Furthermore, VC and OP can regulate each other, promoting the occurrence and progression of both conditions. On the one hand, VC can lead to narrowing of the vascular lumen, thereby affecting blood perfusion in bone tissues and reducing bone matrix synthesis. On the other hand, various regulatory factors and matrix vesicles secreted by bone cells can not only regulate the process of bone mineralization but also promote VC by inducing the phenotypic transdifferentiation of vascular smooth muscle cells (VSMC) into osteoblast-like cells. In-depth research into the underlying molecular mechanisms of the “calcification paradox” holds promise for providing new insights and therapeutic targets for developing drug interventions that simultaneously improve bone and vascular health.

Abstract:Vascular fibrosis is the core pathological process of cardiovascular disease progression, which is characterized by abnormal deposition and remodeling of extracellular matrix (ECM) in the vascular wall. This results in the loss of vascular elasticity, hemodynamic derangement, and end-organ damage. This process involves the phenotypic transformation of vascular smooth muscle cell (VSMC), endothelial-mesenchymal transition (EndMT), and activation of inflammatory-fibrotic networks. The mechanisms include multicellular interactions, signaling pathway crosstalk, and epigenetic regulation. This article systematically reviews the pathophysiological basis, key molecules and signaling networks of vascular fibrosis, discusses potential therapeutic targets and clinical translation challenges based on current research status, and provides an outlook on future development directions.