Inhibiting MicroRNA-29a Protects Myocardial Ischemia-Reperfusion Injury by Targeting SIRT1 and Suppressing Oxidative Stress and NLRP3-Mediated Pyroptosis Pathway.

To investigate the effects of microRNA-29a (miR-29a) on myocardial ischemia-reperfusion (I/R) injury and its specific mechanisms, we used H9C2 myocardial cells to establish a myocardial ischemia model by hypoxia/reoxygenation (H/R), and microRNA-29a inhibitor was interfered. Annexin V/propidium iodide and flow cytometry were used to detect the effects of cell death. C57 mice were used to establish were used to establish the I/R injury model, and H&E staining was used to detect pathologic damage to heart tissues. The expressions of miR-29a silent information regulator factor 2-related enzyme 1 (SIRT1) and nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3), as well as pyroptosis-related proteins were determined by quantitative reverse-transcription polymerase chain reaction and Western blot analysis. The serum levels of 2-hydroxybutyrate dehydrogenase (HBDH), lactate dehydrogenase-1 (LDH), creatine kinase (CK), creatine kinase MB activity (CK-MB), IMA, and inflammatory factors in I/R rats were significantly up-regulated. In the I/R group, the expression of miR-29a was significantly up-regulated while SIRT1 was remarkably down-regulated. Dual luciferase reporter assay showed SIRT1 was a direct target of miR-29a. Inhibition of miR-29a significantly up-regulated the expression of peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor-2 and endothelial nitric oxide synthase while remarkably down-regulating levels of inducible nitric oxide synthase and malondialdehyde in I/R. The oxidative stress that was induced by I/R injury was also suppressed by inhibition of miR-29a. All these effects of miR-29a inhibition were reversed by small interfering SIRT1. The in vitro H/R results showed that NLRP3-caspase-1-mediated pyroptosis was activated in H/R but was significantly inhibited by the inhibition of miR-29a. Inhibition of miR-29a improved myocardial I/R injury by targeting SIRT1 through suppressing oxidative stress and NLRP3-mediated pyroptosis. SIGNIFICANCE STATEMENT: In this study, we showed for the first time that miR-29a could improve myocardial I/R injury through inhibition of pyroptosis.

Comparative efficacy and safety of lipid-lowering agents in patients with hypercholesterolemia: A frequentist network meta-analysis.

BACKGROUND: The comparative efficacy and safety of PCSK9 inhibitors, statins, and ezetimibe to lower lipid levels in patients with hypercholesterolemia remain unknown. We aimed to investigate the benefits and harms of the lipid-lowering agents in these patients. METHODS: PubMed, Embase, and the Cochrane Library were searched from January 1, 2000 to June 1, 2018 for relevant randomized controlled trials (RCTs). Frequentist network meta-analysis was used to pool all estimates. Ranking probabilities were used to rank the comparative effects of all drugs against placebo. RESULTS: Eighty-four RCTs enrolled 246,706 patients were included. Most of the included were assessed as low risk of bias. The probabilities of PCSK9 inhibitors that ranked first in improving lipid outcomes were all 100%. The probability of statins that ranked first in reducing the risk of cardiovascular (CV) events was 60.6%, and the probability of PCSK9 inhibitor was 37.1%, while no significant difference of efficacy in reducing CV events was observed between the 2 agents (odds ratios [OR] 0.98, 95% CI 0.87-1.11). Statin ranked first in reducing all-cause and CV death. Compared with placebo, statins were associated with reduced risks of all-cause (OR 0.90, 95% CI 0.85-0.96) and CV death (OR 0.83, 95% CI 0.75-0.91) while PCSK9 inhibitors and ezetimibe were not. No agents caused adverse events (including neurocognitive events), except that statins therapy significantly increases the levels of alanine aminotransferase (ALT) (OR 1.89, 95% CI 1.42-2.51) and creatine kinase (CK) (OR 1.45, 95% CI 1.09-1.93) and the incidence of diabetes (OR 1.13, 95% CI 1.02-1.26). CONCLUSIONS: PCSK9 inhibitors were the most effective lipid-lowering agents in improving lipid levels. Furthermore, PCSK9 inhibitors achieved similar CV benefits like statins, while PCSK9 inhibitors were not associated with any increased risk of statin-related side-effects. Thus, PCSK9 inhibitors may also be recommended as promisingly first-line lipid-lowering treatment for patients with hypercholesterolemia, especially for these with statins intolerance or resistance.

Syringic acid inhibits apoptosis pathways via downregulation of p38MAPK and JNK signaling pathways in H9c2 cardiomyocytes following hypoxia/reoxygenation injury.

Syringic acid (SA), a naturally occur-ring O­methy-lated trihydroxybenzoic acid monomer extracted from Dendrobium nobile Lindl., has been demonstrated to attenuate renal ischemia­reperfusion (I/R) injury. However, the role of SA in myocardial I/R injury is unclear. The present study aimed to clarify the cardioprotective effect of SA in myocardial I/R injury in vitro and explore the potential molecular mechanisms. In the present study, it was revealed that pretreatment with SA increased the viability and inhibited oxidant stress in H9c2 cardiomyocytes that had suffered hypoxia/reoxygenation (H/R). SA also markedly downregulated B­cell lymphoma 2 (Bcl­2) expression and inhibited the expression of Bcl­2­like protein 4 (Bax) and cleaved caspase­3 in H9c2 cardiomyocytes induced by H/R. In addition, SA significantly alleviated H/R-induced the phosphorylation of p38 mitogen­activated protein kinase (p38MAPK) and c­Jun N­terminal kinase (JNK) in H9c2 cardiomyocytes. In conclusion, the present study demonstrated that SA inhibits the apoptosis of H9c2 cardiomyocytes following H/R injury via reduced activation of the p38MAPK and JNK signaling pathways. The results support the therapeutic usage of SA in the treatment of myocardial infarction.

Impact of Atorvastatin Combined with Ezetimibe for the Treatment of Carotid Atherosclerosis in Patients with Coronary Heart Disease.

BACKGROUND: This study aimed to investigate the impact of atorvastatin (Ato) combined with ezetimibe (Eze) for the treatment of carotid atherosclerosis in patients with coronary heart disease (CHD). METHODS: One hundred and forty-eight CHD patients with carotid atherosclerosis were divided into the control (Ato alone) and combination (Ato and Eze) groups. The treatment course was 12 months; patient blood lipids, carotid intima-media thickness (CIMT), and carotid plaque area were measured before and after treatment. RESULTS: Twelve months after treatment, there was a decrease in the CIMT, and the horizontal and vertical axes of the carotid plaque areas in both groups, compared to pretreatment values. The serum low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased (p < 0.05). There were statistically significant differences (p < 0.05) in the LDL-C (2.12 ± 0.58 mmol/L vs. 2.63 ± 0.56 mmol/L) and CIMT (1.06 ± 0.12 mm vs. 1.13 ± 0.11 mm) levels between the combination and the control groups after treatment. Compared to the control group, the horizontal (0.18 ± 0.06 cm2 vs. 0.19 ± 0.05 cm2) and vertical carotid arterial plaque areas (0.40 ± 0.15 cm2 vs. 0.41 ± 0.17 cm2) of the combination group were reduced after treatment. However, the difference was not statistically significant (p > 0.05). CONCLUSIONS: The combination of Ato and Eze further reduces LDL-C levels and CIMT, and affect the progression of carotid atherosclerosis in CHD patients with hypercholesterolemia.

Effect of cardiac resynchronization therapy on patients with heart failure and narrow QRS complexes: a meta-analysis of five randomized controlled trials.

PURPOSE: Although cardiac resynchronization therapy (CRT) has been demonstrated extensively to benefit heart failure (HF) patients with wide QRS complexes, the effect of CRT in patients with narrow QRS complexes remains unclear. This meta-analysis aimed to determine whether HF patients with narrow QRS complexes may benefit from CRT. METHODS: A search of MEDLINE, EMBASE, and Cochrane databases was performed to identify randomized controlled trials (RCTs) that investigated the effect of CRT in HF patients with narrow QRS complexes (< 130 ms). Outcomes included all-cause mortality, heart failure-related death or hospitalization, 6-min walk distance, quality of life ejection fraction, end-systolic volume, and end-diastolic volume. RESULTS: A total of five RCTs involving 1246 HF patients with narrow QRS complexes were included. The frequency of all-cause mortality for patients receiving CRT versus the control group was 10 versus 7 % (relative risk [RR] 1.45, 95 % confidence interval [CI] 1.002 to 2.091, P = 0.049). CRT did not reduce heart failure-related mortality (RR 0.89; 95 % CI 0.52 to 1.54; P = 0.69) or hospitalization (RR 0.99, 95 % CI 0.79 to 1.23, P = 0.91). In addition, CRT did not improve average 6-min walk distance (weighted mean difference [WMD] 39.28 m, 95 % CI -71.04 to 149.61 m, P = 0.49), QOL scores (WMD 0.64 points, 95 % CI -2.15.10 to 3.43 points, P = 0.65), or ejection fraction (WMD 0.90 %, 95 % CI -0.71 to 2.51 %, P = 0.28). CONCLUSIONS: In HF patients with reduced left ventricular ejection fraction (≤ 35 %) and narrow QRS complexes (< 130 ms), CRT did not improve clinical or functional outcomes and may actually increase all-cause mortality.