Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives

Hyperlipidemia characterized by abnormal deposition of cholesterol in arteries can cause atherosclerosis and coronary artery occlusion, leading to atherosclerotic coronary heart disease. The body prevents atherosclerosis by reverse cholesterol transport to mobilize and excrete cholesterol and other lipids. Apolipoprotein A1, the major component of high-density lipoprotein, plays a key role in reverse cholesterol transport. Here, we reviewed the role of apolipoprotein A1-targeting molecules in antiatherosclerosis therapy, in particular ATP-binding cassette transporter A1, lecithin-cholesterol acyltransferase, and scavenger receptor class B type 1.

Effect of Rho-Kinase and Autophagy on Remote Ischemic Conditioning-Induced Cardioprotection in Rat Myocardial Ischemia/Reperfusion Injury Model

Objective. Remote ischemic conditioning (RIC) is a cardioprotective method in ischemia/reperfusion (I/R) injury. This study investigated the mechanism of Rho-kinase-mediated autophagy in RIC. Methods. Sixty male Sprague–Dawley rats were randomly divided into six groups: sham, I/R, RIC, I/R+fasudil, RIC+wortmannin, and RIC+fasudil+wortmannin. Throughout the experiment, mean arterial pressure and heart rate were continuously monitored. Histopathology and ultrastructure and myocardial enzymes’ expression were evaluated to determine the degree of cardiac injury. The protein expression of the Rho-kinase substrates myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1), autophagy-related protein light chain 3-II (LC3-II) and Beclin 1, and protein kinase B (AKT) was measured in the myocardial tissue. Results. Compared with the sham group, the mean arterial pressure and heart rate were decreased, myocardial enzyme levels were increased, and myocardial damage was aggravated in the I/R group; however, RIC improved these alterations. The expression of phosphorylated MLC and MYPT1 was lower, while LC3-II, Beclin 1, and phospho-AKT expression levels were higher in the RIC group compared with the I/R group. Obviously, treatment of the I/R group rats with fasudil, a Rho-kinase inhibitor, significantly ameliorated the I/R effects, whereas treatment of the RIC group rats with wortmannin, a phosphatidylinositol-3 kinase (PI3K) inhibitor, inhibited the RIC protective effects. Moreover, the rats in the RIC+fasudil+wortmannin group showed similar changes to those in the RIC+wortmannin group. Conclusion. These results showed that RIC protected the myocardium from I/R injury by suppressing Rho-kinase and the underlying mechanism may be related to enhancing autophagy via the PI3K/AKT pathway.

Butein Inhibits Oxidative Stress Injury in Rats with Chronic Heart Failure via ERK/Nrf2 Signaling

Background. Chronic heart failure (CHF) is a serious heart disease resulting from cardiac dysfunction. Oxidative stress is an important factor in aging and disease. Butein, however, has antioxidant properties. To determine the effect of butein on oxidative stress injury in rats, a CHF rat model was established. Methods. The CHF rat model was induced by abdominal aortic coarctation (AAC). Rats in CHF+butein and sham+butein group were given 100 mg/kg butein via gavage every day to detect the effect of butein on oxidative stress injury and myocardial dysfunction. The cardiac structural and functional parameters, including the left ventricular end-systolic dimension (LVESD), the left ventricular end-diastolic dimension (LVEDD), the left ventricular ejection fraction (LVEF), and the left ventricular fractional shortening (LVFS), were measured. Oxidative stress was measured through the production of reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA). Cardiac injury markers like creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) were evaluated. Hematoxylin and eosin (H&E) staining was used to observe the myocardial cell morphology. The effect of butein on the extracellular signal-regulated kinase (ERK)/nuclear factor-E2 p45-related factor (Nrf2) signaling was confirmed by Western blot analysis. Results. Butein had a significant effect on CHF in animal models. In detail, butein inhibited oxidative stress, relieved cardiac injury, and alleviated myocardial dysfunction. Importantly, butein activated the ERK1/2 pathway, which contributed to Nrf2 activation and subsequent heme oxygenase-1 (HO-1) and glutathione cysteine ligase regulatory subunit (GCLC) induction. Conclusions. In this study, butein inhibits oxidative stress injury in CHF rat model via ERK/Nrf2 signaling pathway.

Eligibility of Dapagliflozin and Empagliflozin in a Real-World Heart Failure Population

Aims. This study is aimed at investigating the eligibility in a real-world heart failure population for the DAPA-HF (testing dapagliflozin) and EMPEROR-reduced (testing empagliflozin) trials, comparing the eligible real-world patients to trial participants and to characterize the noneligible patients. Methods. Medical records of all heart failure patients who had a diagnosis of heart failure from the Heart Centre or Department of Internal Medicine at Umeå University Hospital were reviewed. Results. 2433 of the hospital’s uptake population of 150 000 had a diagnosis of heart failure. 681 patients had left ventricle ejection fraction ≤ 40 % , and of these 352 (52%) and 268 (39%) patients met eligibility criteria for DAPA-HF and EMPEROR-reduced, respectively. Comparing eligible patients in our population with the DAPA-HF- and EMPEROR-reduced trial populations, we found that eligible real-world patients were older (79.0 vs. 66.2 years and 80.3 vs. 67.2 years, respectively), had worse renal function (eGFR 54.4 vs. 66.0 ml/min/1.73m2 and 49.5 vs. 61.8 ml/min/1.73m2, respectively), higher prevalence of atrial fibrillation (56.0% vs. 36.1% and 53.0% vs. 35.6%, respectively), and lower prevalence of diabetes mellitus (21.0% vs. 41.8% and 26.1% vs. 49.8%, respectively). The main reasons for ineligibility were low NT-proBNP or low eGFR. Noneligible patients differed according to reason for ineligibility, where patients with low NT-proBNP were generally younger and healthier, and patients with low eGFR were older and had more comorbidities. Conclusions. 39-52% of patients with heart failure and reduced ejection fraction in this real-world heart failure population were eligible for SGLT2-inhibitor treatment, corresponding to 11-14% of all heart failure patients. Compared to trial participants, eligible real-world patients were significantly older with worse renal function, more atrial fibrillation, and less diabetes mellitus. Trial entry criteria exclude comparatively young and healthy patients, as well as comparatively old patients with more comorbid conditions.

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the regulation of LDL metabolism. There is evidence that circulating PCSK9 is a cardiovascular risk factor. In this study, we determined factors associated with circulating PCSK9 in a group of patients with type 2 diabetes mellitus (DM2). Material included 116 consecutive patients with DM2 from outpatient diabetes clinic. Circulating PCSK9, PTX3, apolipoprotein (apo) B100, apo B48, and apo C3 levels were determined by ELISA, apo A1 by immunoturbidimetry. The mean (sd) age of patients was 59.1 (11.1) years, the mean (sd) values of serum PCSK9 were 255.4 (106.97) ng/ml. Circulating PCSK9 correlated negatively with age ( r = − 0.21 , p < 0.05 ) and HbA1c ( r = − 0.21 , p < 0.05 ) and positively with BMI ( r = 0.21 , p < 0.05 ), total cholesterol ( r = 0.59 ), LDL-cholesterol ( r = 0.50 ), triglyceride ( r = 0.35 ), apo B100 ( r = 0.43 ), apo A1 ( r = 0.43 ) ( p < 0.001 for all), apo C3 ( r = 0.29 , p < 0.01 ), and apo B48 ( r = 0.25 , p < 0.01 ) concentration and FLI ( r = 0.26 , p < 0.01 ). Strong correlation between PTX3 and PCSK9 levels was observed ( r = 0.47 , p < 0.001 ). Multiple stepwise backward regression analysis with PCSK9 as dependent variable revealed that PTX3, apo B100, apo A1, apo B48, and BMI were significantly positive and the presence of NAFLD and HbA1c negatively associated with PCSK9 concentrations. These variables together explain 57% of PCSK9 variability; the strongest relationship was observed between PCSK9 and PTX3 and apo B100. Our results indicate that circulating PCSK9 is significantly associated with inflammation marker PTX3 as well as atherogenic lipids and apolipoproteins C3, B100, and B48, which might be of value in understanding interactions between development of atherosclerosis and inflammatory state in DM2 patients.

Clinical Nomogram to Predict Major Adverse Cardiac Events in Acute Myocardial Infarction Patients within 1 Year of Percutaneous Coronary Intervention

The purpose of this study was to summarize the clinical characteristics and risk factors of major adverse cardiovascular events (MACEs) in patients who had had acute myocardial infarction (AMI) within 1 year of percutaneous coronary intervention (PCI). A total of 421 AMI patients who were treated with PCI and experienced MACEs within 1 year of their admission were included in this retrospective study. In addition, patients were matched for age, sex, and presentation with 561 patients after AMI who had not had MACEs. The clinical characteristics and risk factors for MACEs within 1 year in AMI patients were investigated, to develop a nomogram for MACEs based on univariate and multivariate analyses. The C statistic was used to assess the discriminative performance of the nomogram. In addition, calibration curve and decision curve analyses were conducted to validate the calibration performance and utility, respectively, of the nomogram. After univariate and multivariate analyses, a nomogram was constructed based on age (odds ratio (OR): 1.030; 95% confidence interval (CI): 1.014–1.047), diabetes mellitus (OR: 1.667; 95% CI: 1.151–2.415), low-density lipoprotein cholesterol (OR: 1.332; 95% CI: 1.134–1.565), uric acid (OR: 1.003; 95% CI: 1.001–1.005), lipoprotein (a) (OR: 1.003; 95% CI: 1.002–1.003), left ventricular ejection fraction (OR: 0.929; 95% CI: 0.905–0.954), Syntax score (OR: 1.075; 95% CI: 1.053–1.097), and hypersensitive troponin T (OR: 1.002; 95% CI: 1.002–1.003). The C statistic was 0.814. The calibration curve showed good concordance of the nomogram, while decision curve analysis demonstrated satisfactory positive net benefits. We developed a convenient, practical, and effective prediction model for predicting MACEs in AMI patients within 1 year of PCI. To ensure generalizability, this model requires external validation.

The Anti-Inflammatory and Antiapoptotic Effects of Nicorandil in Antisepsis Cardiomyopathy

Objective. To observe the effect of nicorandil on septic rats and explore the possible mechanism of its myocardial protection, so as to provide theoretical basis for the treatment of septic cardiomyopathy. Methods. Sixty male clean SD rats were selected as the research objects and randomly divided into 3 groups by random number method: sham operation group (sham group), cecal ligation and perforation group (CLP group), nicorandil treatment group (nicorandil+CLP group). After the operation, the nicorandil group was pumped with nicorandil diluent 1 ml/h (2 mg/kg/h) with a micropump for 6 hours. The sham group and CLP group were pumped with the same amount of normal saline 1 ml/h for a total of 6 hours. After 24 hours, the survival of the rats in each group was observed. The expression of troponin I (cTnI), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) in the serum was detected. Then, the ventricle was harvested for the observation of the pathological changes of myocardium. Quantitative real-time polymerase chain reaction and immunostaining were used to detect myocardial tissue apoptosis, and Western blot methods were used to detect protein expression changes in nuclear factor-κB (NF-κB) pathways. Results. 24 hours after operation, the survival rate of the rats in the CLP group was 60%. There was a large amount of necrosis of myocardial cells and inflammatory cell infiltration. The survival rate of rats in the nicorandil+CLP group was 75%. Compared with the CLP group, the necrosis of myocardial cells was reduced, and there was still a small amount of inflammatory cell infiltration. In the CLP group, myocardial inflammation and apoptosis were significant, and NF-κB pathway was activated. On the contrary, the NF-κB pathway in the nicorandil+CLP group was inhibited, and the expression of inflammatory factors and apoptosis factors was inhibited. Conclusion. Nicorandil can reduce the release of inflammatory factors in septic rats, improve the inflammatory response, reduce myocardial damage, and play a myocardial protective effect. Its mechanism may be related to the inhibition of the activation of NF-κB signaling pathway.

CTRP9 Mitigates the Progression of Arteriovenous Shunt-Induced Pulmonary Artery Hypertension in Rats

The present study is aimed at investigating the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) and providing a new perspective in arteriovenous shunt-induced pulmonary arterial hypertension (PAH). PAH was established by an arteriovenous shunt placement performed in rats. Adenovirus(Ad)-CTRP9 and Ad-green fluorescent protein viral particles were injected into the rats through the tail vein. Following 12 weeks, the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured and morphological analysis was conducted to confirm the establishment of the PAH model. The systemic elevation of CTRP9 maintained pulmonary vascular homeostasis and protected the rats from dysfunctional and abnormal remodeling. CTRP9 attenuated the pulmonary vascular remodeling in the shunt group by decreasing the mPAP and RVSP, which was associated with suppressed inflammation, apoptosis, and extracellular matrix injury. In addition, CTRP9 dramatically increased the phosphorylation of AKT and p38-MAPK in the lung tissues of shunt-operated animals. These findings suggest a previously unrecognized effect of CTRP9 in pulmonary vascular homeostasis during PAH pathogenesis.

The Association between the Serum Uric Acid Level and Hypertension in Middle-Aged and Elderly Adults

Background. Studies on serum uric acid (sUA) levels and hypertension (HTN) are controversial. To investigate the association between the sUA level and the incident of HTN in middle-aged and elderly adults, we performed this study. Methods. 6399 participants aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) were included. Weighted multiple logistic regression analysis was carried out to evaluate the relationship between the sUA level and the incident of HTN, exploring the potential nonlinear relationship using the fitted smoothing curves. If nonlinearity was observed, the inflection point was further calculated by a recursive algorithm. Results. A positive relationship between the sUA level and the incident of HTN was found. However, it may differ in different race groups, nor between male and female. Moreover, the association between the sUA level and the incident of HTN followed a U-shaped curve in male (turning point: sUA 4.1 mg/dL) and Whites (turning point: sUA 7.9 mg/dL). Conclusions. The results revealed that the sUA level is positively correlated with the incident of HTN, in middle-aged and elderly adults. However, it followed a U-shaped curve in males and Whites.

MicroRNA-146a Serves as a Biomarker for Adverse Prognosis of ST-Segment Elevation Myocardial Infarction

Objective. This study is aimed at exploring the underlying molecular mechanisms of ST-segment elevation myocardial infarction (STEMI) and provides potential clinical prognostic biomarkers for STEMI. Methods. The GSE60993 dataset was downloaded from the GEO database, and the differentially expressed genes (DEGs) between STEMI and control groups were screened. Enrichment analysis of the DEGs was subsequently performed using the DAVID database. A protein–protein interaction network was constructed, and hub genes were identified. The hub genes in patients were then validated by quantitative reverse transcription-PCR. Furthermore, hub gene-miRNA interactions were evaluated using the miRTarBase database. Finally, patient data on classical cardiovascular risk factors were collected, and plasma microRNA-146a (miR-146a) levels were detected. An individualized nomogram was constructed based on multivariate Cox regression analysis. Results. A total of 239 DEGs were identified between the STEMI and control groups. Expression of S100A12 and miR-146a was significantly upregulated in STEMI samples compared with controls. STEMI patients with high levels of miR-146a had a higher risk of major adverse cardiovascular events (MACEs) than those with low levels of miR-146a (log-rank P = 0.034 ). Multivariate Cox regression analysis identified five statistically significant variables, including age, hypertension, diabetes mellitus, white blood cells, and miR-146a. A nomogram was constructed to estimate the likelihood of a MACE at one, two, and three years after STEMI. Conclusion. The incidence of MACEs in STEMI patients expressing high levels of miR-146a was significantly greater than in those expressing low levels. MicroRNA-146a can serve as a biomarker for adverse prognosis of STEMI and might function in its pathogenesis by targeting S100A12, which may exert its role via an inflammatory response. In addition, our study presents a valid and practical model to assess the probability of MACEs within three years of STEMI.