Bang-Dang Chen

The preprotein convertase, Bacillus subtilis protease/kexin type 9 serine protease (PCSK9), has garnered significant attention as a potential lipid lowering and therapeutic drug target for atherosclerosis (AS). Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in various tissues and has crucial roles in lipid metabolism and the inflammatory response; however, the precise impact of PCSK9 on AS progression through its regulation of PPARα remains uncertain. The present study aimed to examine the impact of introducing stable liver transduction of human derived PCSK9 with a gain of function D374Y mutation (PCSK9^DY) into systemic PPARα knockout mice (PPARα^−/−) on plasma lipid levels and AS. Enzymatic assays were employed to evaluate plasma lipid concentrations at various time points, and aortic plaque formation and the degree of inflammatory infiltration quantified. Subsequently, we validated our in vivo results using mouse primary peritoneal macrophages (MPMs). Furthermore, AAV8.2-PPARα virus vector was transduced into transgenic mice of human PCSK9(hPCSK9^DY-Tg) by tail vein, and the changes of plasma lipid level and AS were detected. PCSK9^DY expression exacerbated symptoms of hypercholesterolemia in PPARα^−/− mice. En face analysis and quantification of aortic root sections demonstrated a significant increase in aortic plaque area and inflammatory infiltration in PCSK9^DY transduced PPARα^−/− mice. Secretion of inflammatory cytokines was elevated in PCSK9^DY transduced PPARα^−/− mice. In vitro, recombinant hPCSK9 protein promotes the foam cell formation and inflammatory cytokines secretion of PPARα^−/− MPMs by increasing the expression of SR-A and TLR4/NF-κB pathway proteins. AAV8.2-PPARα virus vector can reduce the plasma lipid level and AS formation in hPCSK9^DY-Tg mice. These finding demonstrate that PCSK9^DY expression notably facilitated AS progression in PPARα^−/− mice by increasing plasma lipid concentrations and inflammation. However, overexpression of PPARα can reduce AS formation in hPCSK9^DY-Tg mice.

Purpose To investigate the protective effect and mechanism of enhanced expression of endogenous macrophage migration inhibitory factor (MIF) on cardiac ischemia–reperfusion (I/R) injury. Methods A recombinant double-stranded adeno-associated virus serotype 9 with MIF or green fluorescent protein (GFP) genes (dsAAV9-MIF/GFP) was transduced into mice and neonatal rat ventricular myocytes (NRVMs). The models of cardiac 60 min ischemia and 24 h reperfusion and 12 h hypoxia/12 h reoxygenation (H/R) were established in mice and NRVMs, respectively. Infarct size, cardiac remodeling, and related signaling pathways were assessed. Results The dsAAV9 vector demonstrated strong transduction efficacy and cardiac affinity. Cardiac overexpression of MIF led to a 35.3% reduction in infarct size and improved cardiac function following I/R injury. In the dsAAV9-MIF group, the AMP-activated protein kinase (AMPK) signaling pathway was activated, and autophagy was enhanced during the ischemic period. During reperfusion, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway was upregulated, leading to reduced cardiac apoptosis. In vitro, transfection with MIF in NRVMs also upregulated AMPK and ERK1/2 signaling during hypoxia and reoxygenation, respectively. Furthermore, MIF overexpression significantly improved autophagy and mitochondrial function, evidenced by an increased LC3-II/I ratio and enhanced mitochondrial membrane potential (ΔΨm), with these effects reversed by the AMPK inhibitor compound C. Additionally, MIF overexpression led to a 60% reduction in the apoptosis rate of cardiomyocytes subjected to H/R and decreased the Bax/Bcl-2 ratio, partially through the ERK1/2 signaling pathway. Conclusion Enhanced endogenous MIF expression via the dsAAV9 vector provides significant cardioprotection against I/R injury by activating the AMPK and ERK1/2 signaling pathways. Our findings suggest that targeting MIF may represent a viable therapeutic strategy for severe and prolonged I/R injury.

Background: The present study was aimed to establish a prediction model for in-stent restenosis (ISR) in subjects who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). Materials and methods: A retrospective cohort study was conducted. From September 2010 to September 2013, we included 968 subjects who had received coronary follow-up angiography after primary PCI. The logistic regression analysis, receiver operator characteristic (ROC) analysis, nomogram analysis, Hosmer–Lemeshow χ² statistic, and calibration curve were applied to build and evaluate the prediction model. Results: Fifty-six patients (5.79%) occurred ISR. The platelet distribution width (PDW), total cholesterol (TC), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and lesion vessels had significant differences between ISR and non-ISR groups (all P < 0.05). And these variables were independently associated with ISR (all P < 0.05). Furthermore, they were identified as predictors (all AUC > 0.5 and P < 0.05) to establish a prediction model. The prediction model showed a good value of area under curve (AUC) (95%CI): 0.72 (0.64–0.80), and its optimized cut-off was 6.39 with 71% sensitivity and 65% specificity to predict ISR. Conclusion: The incidence of ISR is 5.79% in CAD patients with DES implantation in the Xinjiang population, China. The prediction model based on PDW, SBP, TC, LDL-C, and lesion vessels was an effective model to predict ISR in CAD patients with DESs implantation.

PCSK9 plays a crucial role in lipid metabolism. This case–control study explored the associations of novel single nucleotide polymorphisms (SNPs) of the PCSK9 gene with coronary artery disease (CAD) (≥ 1 coronary artery stenosis ≥ 50%) and its risk factors in the Han population in Xinjiang, China. Four tag SNPs (rs11583680, rs2483205, rs2495477 and rs562556) of the PCSK9 gene were genotyped in 950 CAD patients and 1082 healthy controls. The distributions of genotypes in rs2483205 and rs562556 were significantly different between the groups (all p < 0.05). The TT genotype of rs2483205, GG genotype of rs562556, and their H4 (T-G) haplotype were associated with CAD [odds ratio (OR) 0.65, confidence interval (CI) 0.45–0.95, p = 0.024; 0.63, 0.45–0.90, p = 0.011; 0.50, 0.35–0.70, p < 0.001, respectively]. Additionally, the model (TT + CT vs. CC) of rs2483205 was associated with increased risk of obesity, and the G allele of rs562556 was associated with lower low-density lipoprotein cholesterol (LDL-C), blood glucose, body mass index (BMI), and mean platelet volume (MPV) (all p < 0.05). rs2483205, rs562556, and their H4 haplotype of the PCSK9 gene were associated with CAD. Additionally, rs2483205 is associated with obesity, and rs562556 is associated with LDL-C, blood glucose, BMI, and MPV.

PCSK9 plays a pivotal role in lipid metabolism. The present study is to explore the potential novel single nucleotide polymorphisms (SNPs) of the PCSK9 gene which is associated with coronary artery disease (CAD) in the Han population who lived in Xinjiang, China. We conducted a case-control study and genotyped four tag SNPs of the PCSK9 gene in 950 CAD and 1082 health subjects in the Han population. This study showed that for rs2483205, the distributions in genotypes had significant differences between the CAD and control groups (p = 0.025), and the subjects with TT genotype had lower total cholesterol (TC) level than CT genotype (p = 0.025). For rs562556, there were significant differences between the CAD and control groups for distributions of genotypes (p = 0.020), and the individuals with a G allele had a lower low-density lipoprotein cholesterol (LDL-C) level than an A allele (p = 0.048). Furthermore, the TT genotype of rs2483205 and GG genotype of rs562556 were independently associated with CAD (odds ratio [OR] = 0.53, 95% confidence interval [CI] = 0.29-0.95, p = 0.032 and OR = 0.57, 95%CI = 0.34-0.95, p = 0.032, respectively). In conclusion, the rs2483205 and rs562556 were significantly associated with CAD.

Background: Aged patients suffering from acute myocardial ischemia (AMI) exhibit an increased mortality rate and worse prognosis, and a more effective treatment is currently in need. In the present study, we investigated potent targets related to Wnt/β-catenin pathway deregulation for AMI injury treatment. Methods: In the present study, AAV-Sfrp1 was transduced into the myocardium of aged mice, and an AMI model was established in these aged mice to study the effect and molecular mechanism of Sfrp1 overexpression on AMI-induced injury. Results: The results showed that Sfrp1 was successfully overexpressed in the myocardium of aged mice and remarkably reduced Wnt/β-catenin pathway activity in aged mice after AMI, effectively reducing the degree of myocardial fibrosis, inhibiting cardiomyocyte apoptosis, and improving cardiac function. We revealed that the exogenous introduction of Sfrp1 could be considered a promising strategy for improving post-AMI injury in aged mice by inhibiting Wnt/β-catenin pathway activity. Conclusions: In conclusion, the Wnt/β-catenin pathway potentially represents a key target in AMI in aged mice. Sfrp1 might be used as a small molecule gene therapy drug to improve heart function, reduce the degree of myocardial fibrosis, inhibit cardiomyocyte apoptosis and reduce AMI injury in aged mice by inhibiting the Wnt/β-catenin pathway, thereby effectively protecting aged hearts from AMI injury.