High density lipoprotein (HDL) cholesterol levels and cholesterol efflux capacity (CEC) are inversely correlated with coronary artery disease (CAD) risk. Myeloperoxidase (MPO) derived oxidants and HDL proteome changes are implicated in HDL dysfunction in subjects with CAD in the United States; however, the effect of MPO on HDL function and HDL proteome in ethnic Chinese population is unknown. We recruited four matched ethnic Chinese groups (20 patients each): subjects with 1) low HDL levels (HDL levels in men <40mg/dL and women <50mg/dL) and non-CAD (identified by coronary angiography or cardiac CT angiography); 2) low HDL and CAD; 3) high HDL (men >50mg/dL; women >60mg/dL) with no CAD; and 4) high HDL with CAD. Serum cytokines, serum MPO levels, serum CEC, MPO-oxidized HDL tyrosine moieties, and HDL proteome were assessed by mass spectrometry individually in the four groups. The cytokines, MPO levels, and HDL proteome profiles were not significantly different between the four groups. As expected, CEC was depressed in the entire CAD group but more specifically in the CAD low-HDL group. HDL of CAD subjects had significantly higher 3-nitrotyrosine than non-CAD subjects, but the MPO-specific 3-chlorotyrosine was unchanged; CEC in the CAD low-HDL group did not correlate with either HDL 3-chlorotyrosine or 3-nitrotyrosine levels. Neither 3-chlorotyrosine, which is MPO-specific, nor 3-nitrotyrosine generated from MPO or other reactive nitrogen species was associated with CEC. MPO mediated oxidative stress and HDL proteome composition changes are not the primary cause HDL dysfunction in Chinese subjects with CAD. These studies highlight ethnic differences in HDL dysfunction between United States and Chinese cohorts raising possibility of unique pathways of HDL dysfunction in this cohort.

Early identification for heart failure (HF) may be useful for disease modifying treatment in order to reduce heart disease progression or even to reverse it. In our previous studies, we have revealed a group of heat shock proteins (HSPs) which might be related to neonatal rat cardiomyocyte hypertrophy by proteomic approach. Here, we confirm that HSPs, including HSP27 and HSP70, altered in the early stage of cardiac remodeling in vivo animal model. Furthermore, plasma concentrations of those HSPs and their potential screening value were evaluated at different stages in 222 patient subjects. Plasma HSP27, HSP70 and HSP90 were measured using enzyme-linked immunosorbent assay. Results indicate that HSP70 was positively correlated to the severity (progression) of HF (r = 0.456, p<0.001). The area under the rate of change (ROC) curve was 0.601 (p = 0.017) in patients with stage B HF and 0.835 (p<0.001) in those with stage C HF. However, HSP27 and HSP90 did not display significant changes in any stage of HF in this study. Taken together, plasma concentrations of HSP70 elevated with the progression of HF and might act as a potential screening biomarker for early diagnosis of HF.

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10(-7)), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci-PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser-also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography-tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.

Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2-/-) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the β-adrenergic receptor (β-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2-/- mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2-/- mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear.

The metalloproteinase family of a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7) was reported to be a novel locus associated with human coronary artery disease. This study aimed to investigate plasma ADAMTS-7 levels in stable obstructive CAD patients and elucidate the relationship between plasma ADAMTS-7 levels and the severity of CAD assessed by the Syntax score.This was a single center cross-sectional study performed in 182 CAD patients. ELISA was used to measure plasma ADAMTS-7 levels. All patients were divided into subgroup according to the ADAMTS-7 median in this cohort: high group with ADAMTS-7 ≥0.99 ng/mL and low group with ADAMTS-7 <0.99 ng/mL. Furthermore, all patients were divided into tertiles according to their Syntax scores (low group: Syntax score ≤10.0; moderate group: 10.0 18.0). We followed up the participants continuously until the first major adverse cardiovascular event (MACE) for a mean time of 22.0 months.Plasma ADAMTS-7 levels in the high Syntax score group were significantly higher compared with the low Syntax score group (3.29 [0.08-26.3] ng/mL vs 1.24 [0.15-8.78] ng/mL, P = 0.010). Plasma ADAMTS-7 levels were significantly positively correlated with the Syntax score tertiles (r = 0.157, P = 0.035). Logistic regression analysis indicated that the plasma ADAMTS-7 level was one of the independent predictors for the Syntax score tertiles (B = 1.118, 95% CI: 1.194-7.830, P = 0.020), together with HbA1c (B = 0.946, 95% CI: 1.248-5.312, P = 0.010), uric acid (B = -0.019, 95% CI: 0.974-0.988, P<0.001), and coronary artery calcium score (B = -0.001, 95% CI: 0.998-0.999, P < 0.001). Compared with the low ADAMTS-7 group, the high ADAMTS-7 group had significantly higher Syntax score (17.10±8.42 vs 14.96 ± 8.11, P = 0.047). Kaplan-Meier analysis showed patients in the high plasma ADAMTS-7 group tend to have a lower event-free survival rate than patients in the low plasma ADAMTS-7 group, unfortunately, no difference was detected (86.8% vs 88.0%, log rank = 0.314, P = 0.575).The plasma ADAMTS-7 level was positively correlated with the Syntax score significantly. The elevated plasma ADAMTS-7 level may be involved in the severity of disease in patients with stable coronary artery disease.

Neuregulin-1 (NRG-1) is reported to be cardioprotective through the extracellular-regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia-reperfusion injury (MIRI). NOX4-induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG-1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase-1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC-Evans blue staining. Immunohistochemical staining, real-time quantitative PCR (RT-qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase-1 and IL-1β .The IS in the NRG-1 (3 μg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG-1 decreased 4HNE and NOX4. The RT-qPCR and Western blot analyses revealed that NRG-1 mitigated the IR-induced up-regulation of NOX4 and ROS production. Compared with the IR group, the NRG-1 group exhibited a higher level of P-ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up-regulated the expression of NOX4, NLRP3, caspase-1 and IL-1β, which exacerbated oxidative stress and inflammation. In conclusion, NRG-1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase-1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

Enhanced External Counterpulsation (EECP) can chronically relieve ischemic chest pain and improve the prognosis of coronary heart disease (CHD). Despite its role in mitigating heart complications, EECP and the mechanisms behind its therapeutic nature, such as its effects on blood flow hemodynamics, are still not fully understood. This study aims to elucidate the effect of EECP on significant hemodynamic parameters in the coronary arterial tree.

The action of β-adrenergic receptors (β-ARs) induces cardiac fibroblast (CF) proliferation and collagen synthesis and is a major source of the cardiac fibrosis caused by various diseases. Recently, microRNA-214 (miR-214) was found to play an important role in the pathogenesis of cardiac remodelling. In the present study, we examined the role and the underlying mechanism of miR-214 in isoproterenol (ISO, a β-AR agonist)-induced CF proliferation and collagen synthesis. The expression of miR-214 was increased in both ISO-mediated fibrotic heart tissue and fibroblasts. Downregulation of miR-214 by antagonists attenuated the proliferation and collagen synthesis in ISO-treated CFs. Using bioinformatics analysis and luciferase assays, mitofusin2 (Mfn2), a critical regulator of cell proliferation and tissue fibrosis, was identified as a direct target gene of miR-214; this result was confirmed by western blot analysis. Additionally, corresponding to the upregulation of miR-214, the expression of Mfn2 was downregulated in the fibrotic heart and fibroblasts. Furthermore, the downregulation of miR-214 inhibited the activation of ERK1/2 MAPK signalling induced by ISO treatment. In conclusion, our study demonstrated that miR-214 mediates CF proliferation and collagen synthesis via inhibition of Mfn2 and activation of ERK1/2 MAPK signalling, which provides a new explanation for the mechanism of β-AR activation-induced cardiac fibrosis.

The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP).

MicroRNA 711 (miR-711) levels in the heart change dynamically after myocardial infarction (MI). As peroxisome proliferator-activated receptor gamma (PPARγ) can upregulate miR-711 in adipocytes and cardiac fibroblasts, this study examined the precise mechanism of PPARγ-mediated miR-711 upregulation and its role in the heart in the early stages after MI. In a rat model of MI induced by left anterior descending coronary artery ligation, immunohistochemical and western blot analyses revealed increased PPARγ expression in cardiomyocyte nuclei after MI. PPARγ modulated miR-711 levels in neonatal rat cardiomyocytes, and chromatin immunoprecipitation and luciferase assays revealed that it bound the premiR-711 promoter to upregulate miR-711. Bioinformatics analysis identified calnexin as a putative miR-711 target; this was confirmed by luciferase, western blot, and real-time polymerase chain reaction analyses. Additionally, the transfection of a miR-711 mimic into cardiomyocytes induced the endoplasmic reticulum (ER) stress-induced apoptosis response by upregulating glucose-regulated protein 78 (GRP78), activating transcription factor (ATF6), spliced X-box binding protein 1 (XBP1), apoptotic signal-regulating kinase 1 (ASK1), CCAAT-enhancer binding protein homologous protein (CHOP), caspase-12, and endoplasmic reticulum oxidoreductase 1 alpha (ERO1a). Similarly, on day 2 after MI, increased miR-711 levels in the heart were accompanied by increased cardiomyocyte apoptosis, decreased calnexin levels, and increased levels of GRP78, ATF6, spliced XBP1, ASK1, CHOP, and caspase-12, as well as cardiomyocytes apoptosis. The mechanism underlying these effects may involve the direct binding of PPARγ to the pre-miR-711 promoter for the upregulation of miR-711, which may induce ER stress-mediated cardiomyocyte apoptosis via calnexin. These findings augment the general knowledge of the post-MI pathological process and suggest a therapeutic strategy for cardiac remodelling in the early stages after MI.

Considering the inevitability for humans to be frequently exposed to nanoparticles (NPs), understanding the biosafety of NPs is important for rational usage. As an important part of the innate immune system, macrophages are widely distributed in vital tissues and are also a dominant cell type that engulfs particles. Mitochondria are one of the most sensitive organelles when macrophages are exposed to NPs. However, previous studies have mainly reported the mitochondrial response upon high-dose NP treatment. Herein, with gold nanoparticles (AuNPs) as a model, we investigated the mitochondrial alterations induced by NPs at a sublethal concentration.

Exercise training protects against heart failure. However, the mechanism underlying the protective effect of exercise training on angiotensin II (Ang II)-induced cardiac fibrosis remains unclear.