Tenecteplase versus alteplase in treatment of acute ST-segment elevation myocardial infarction: A randomized non-inferiority trial.

BACKGROUND: A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI. METHODS: In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints. RESULTS: From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a -15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: -3.4%; 95% confidence interval [CI]: -11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: -0.5%; 95% CI: -5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. CONCLUSION: rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI. TRIAL REGISTRATION: www.ClinicalTrials.gov (No. NCT02835534).

[MicroRNA-22-3p Regulates the Expression of Kruppel-like Factor 6 to Affect the Cardiomyocyte-like Differentiation of Bone Marrow Mesenchymal Stem Cell].

Objective To explore the effect of microRNA-22-3p (miR-22-3p) regulating the expression of Kruppel-like factor 6 (KLF6) on the cardiomyocyte-like differentiation of bone marrow mesenchymal stem cell (BMSC). Methods Rat BMSC was isolated and cultured,and the third-generation BMSC was divided into a control group,a 5-azacytidine(5-AZA)group,a mimics-NC group,a miR-22-3p mimics group,a miR-22-3p mimics+pcDNA group,and a miR-22-3p mimics+pcDNA-KLF6 group.Real-time fluorescent quantitative PCR (qRT-PCR) was carried out to determine the expression of miR-22-3p and KLF6 in cells.Immunofluorescence staining was employed to detect the expression of Desmin,cardiac troponin T (cTnT),and connexin 43 (Cx43).Western blotting was employed to determine the protein levels of cTnT,Cx43,Desmin,and KLF6,and flow cytometry to detect the apoptosis of BMSC.The targeting relationship between miR-22-3p and KLF6 was analyzed by dual luciferase reporter gene assay. Results Compared with the control group,5-AZA up-regulated the expression of miR-22-3p (q=7.971,P<0.001),Desmin (q=7.876,P<0.001),cTnT (q=10.272,P<0.001),and Cx43 (q=6.256,P<0.001),increased the apoptosis rate of BMSC (q=12.708,P<0.001),and down-regulated the mRNA (q=20.850,P<0.001) and protein (q=11.080,P<0.001) levels of KLF6.Compared with the 5-AZA group and the mimics-NC group,miR-22-3p mimics up-regulated the expression of miR-22-3p (q=3.591,P<0.001;q=11.650,P<0.001),Desmin (q=5.975,P<0.001;q=13.579,P<0.001),cTnT (q=7.133,P<0.001;q=17.548,P<0.001),and Cx43 (q=4.571,P=0.037;q=11.068,P<0.001),and down-regulated the mRNA (q=7.384,P<0.001;q=28.234,P<0.001) and protein (q=4.594,P=0.036;q=15.945,P<0.001) levels of KLF6.The apoptosis rate of miR-22-3p mimics group was lower than that of 5-AZA group (q=8.216,P<0.001).Compared with the miR-22-3p mimics+pcDNA group,miR-22-3p mimics+pcDNA-KLF6 up-regulated the mRNA(q=23.891,P<0.001) and protein(q=13.378,P<0.001)levels of KLF6,down-regulated the expression of Desmin (q=9.505,P<0.001),cTnT (q=10.985,P<0.001),and Cx43 (q=8.301,P<0.001),and increased the apoptosis rate (q=4.713,P=0.029).The dual luciferase reporter gene experiment demonstrated that KLF6 was a potential target gene of miR-22-3p. Conclusion MiR-22-3p promotes cardiomyocyte-like differentiation of BMSC by inhibiting the expression of KLF6.

4-phenylbutyrate exerts stage-specific effects on cardiac differentiation via HDAC inhibition.

4-phenylbutyrate (4-PBA), a terminal aromatic substituted fatty acid, is used widely to specifically attenuate endoplasmic reticulum (ER) stress and inhibit histone deacetylases (HDACs). In this study, we investigated the effect of 4-PBA on cardiac differentiation of mouse embryonic stem (ES) cells. Herein, we found that 4-PBA regulated cardiac differentiation in a stage-specific manner just like trichostatin A (TSA), a well-known HDAC inhibitor. 4-PBA and TSA favored the early-stage differentiation, but inhibited the late-stage cardiac differentiation via acetylation. Mechanistic studies suggested that HDACs exhibited a temporal expression profiling during cardiomyogenesis. Hdac1 expression underwent a decrease at the early stage, while was upregulated at the late stage of cardiac induction. During the early stage of cardiac differentiation, acetylation favored the induction of Isl1 and Nkx2.5, two transcription factors of cardiac progenitors. During the late stage, histone acetylation induced by 4-PBA or TSA interrupted the gene silence of Oct4, a key determinant of self-renewal and pluripotency. Thereby, 4-PBA and TSA at the late stage hindered the exit from pluripotency, and attenuated the expression of cardiac-specific contractile proteins. Overexpression of HDAC1 and p300 exerted different effects at the distinct stages of cardiac induction. Collectively, our study shows that timely manipulation of HDACs exhibits distinct effects on cardiac differentiation. And the context-dependent effects of HDAC inhibitors depend on cell differentiation states marked by the temporal expression of pluripotency-associated genes.

Wnt3a upregulation is involved in TGFß1-induced cardiac hypertrophy.

Pathological cardiac hypertrophy, characterized by enlarged cell size and fetal gene reactivation, ultimately leads to cardiac dysfunction and heart failure. The expression of transforming growth factor beta 1 (TGFß1) is often elevated in experimental models of cardiac hypertrophy. In the present study, we observed the activation of Wnt/ß-catenin signaling in TGFß1-induced cardiac hypertrophy. TGFß1 stimulation decreased the phosphorylation levels of ß-catenin and triggered the nuclear accumulation of ß-catenin. In turn, TGFß1 enhanced the expression of c-Myc, which is a transcriptional target of canonical Wnt/ß-catenin pathway. Knockdown of ß-catenin completely blocked TGFß1-induced c-Myc upregulation. Wnt3a is an important Wnt ligand associated with cardiac fibrosis and hypertrophy. Further investigation revealed that TGFß1 can upregulate Wnt3a expression in an ALK5-Smad2/3-dependent manner. A consensus Smad binding sequence is located within the Wnt3a promoter, and TGFß1 stimulation enhanced recruitment of Smad2/3 onto the Wnt3a promoter. Meanwhile, Wnt3a overexpression also stimulated TGFß1 expression. Chemical inhibition of Wnt/ß-catenin signaling partially attenuated TGFß1-induced hypertrophic responses. These findings suggest crosstalk between TGFß1 and canonical Wnt/ß-catenin pathways in cardiac hypertrophy.

Spiraeoside protects human cardiomyocytes against high glucose-induced injury, oxidative stress, and apoptosis by activation of PI3K/Akt/Nrf2 pathway.

The present study aimed to explore the effect of spiraeoside, an active quercetin glucoside, on diabetic cardiomyopathy in vitro. Our results showed that spiraeoside attenuated high glucose (HG)-induced reduction of cell viability and increased myocardial enzymes lactate dehydrogenase and aspartate aminotransferase in AC16 cells. Spiraeoside exerted antioxidant activity in HG-induced AC16 cells as spiraeoside inhibited reactive oxygen species and malondialdehyde production and increased activities of superoxide dismutase, glutathione peroxidase, and catalase. Spiraeoside prevented HG-induced apoptosis of AC16 cells. HG stimulation-caused the decrease in the expression levels of p-Akt, nuclear Nrf2, and HO-1 was elevated after spiraeoside treatment in AC16 cells. However, the effects of spiraeoside were reversed by LY294002. In conclusion, spiraeoside protected AC16 cells against HG-induced oxidative stress, cell injury, and apoptosis. The protective effect of spiraeoside was regulated by the PI3K/Akt/Nrf2 signaling pathway.

Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.

Age-related and gender-stratified differences in the association between high triglyceride and risk of hyperuricemia.

BACKGROUND: Elevated serum uric acid is commonly associated with high triglyceride. However, the relation of triglyceride and hyperuricemia in different gender and age groups is currently not well understood. This study aimed to evaluate age- and gender-related association of high triglyceride with hyperuricemia in a subgroup of Chinese population. METHODS: We retrospectively analyzed physical examination data of 24,438 subjects (12,557 men and 11,881 women) in Kaifeng, China. The alanine aminotransferase, γ-glutamyl transpeptidase, serum creatinine, blood urea nitrogen, total cholesterol, high-density lipoprotein cholesterol, triglyceride and serum uric acid were measured in all subjects. The triglyceride was categorized into < 1.21, 1.21 ~, 1.7 ~, 2.83 ~ and >  5.6 mmol/L subgroups, and odds ratio (OR) and 95% confidence interval (CI) of hyperuricemia were calculated by logistic regression analysis. RESULTS: Univariate and age-adjusted analyses showed that high triglyceride was positively associated with hyperuricemia (p <  0.01). Further age-stratified analysis showed that the positive association was significant in the 20 ~, 30 ~, 40 ~, 50 ~, 60 ~ and 80 ~ age groups in men. In women, no statistically significant was found in 60 ~ and 70 ~ age groups. CONCLUSION: High triglyceride is positively associated with hyperuricemia in both men and women, and this association is age-related, especially in women.

The status of MAPK cascades contributes to the induction and activation of Gata4 and Nkx2.5 during the stepwise process of cardiac differentiation.

Cardiac differentiation in vitro is a complex, stepwise process that is rigidly governed by a subset of transcription factors and signaling cascades. In this study, we investigated the cooperation of cardiac-specific transcription factors Gata4 and Nkx2.5, as well as mitogen-activated protein kinase (MAPK) cascades. P19 embryonic carcinoma cells were induced into spontaneously beating cardiomyocytes utilizing a two-step protocol that comprised an early stage and a late stage of differentiation. During early-stage differentiation in suspension culture, P19 cells aggregated to form embryoid bodies (EBs), and the Gata4 and Nkx2.5 genes were induced. However, Gata4 expressed at the early stage of differentiation was incapable of activating downstream gene expression, as it was localized in the cytoplasm and prone to degradation. After EBs were plated for late-stage differentiation in adherent culture, the MAPK cascades were highly activated and contributed to the activation of Gata4 and Nkx2.5. Specifically, we revealed that p38 signaling participated in regulating the localization and stabilization of Gata4 and Nkx2.5. Additionally, the JNK cascade regulated late-stage cardiac differentiation; JNK kinase reduced Gata4 stabilization and conversely alleviated Nkx2.5 degradation by direct interaction and phosphorylation of Nkx2.5. Finally, we found that the C-terminal domain of Nkx2.5 was required for its stabilization under conditions of oxidative stress and JNK activation. Overall, our results indicated that the induction and activation of Gata4 and Nkx2.5 during early- and late-stage cardiac differentiation was closely associated with the function of the MAPK signaling cascades.

Kaempferol alleviates ox-LDL-induced apoptosis by up-regulation of miR-26a-5p via inhibiting TLR4/NF-κB pathway in human endothelial cells.

BACKGROUND: Oxidized low-density lipoprotein (ox-LDL) has been well-documented to induce endothelial cell (EC) apoptosis and contribute to the progression of atherosclerosis. Kaempferol was reported to alleviate ox-LDL-induced apoptosis of human umbilical vein endothelial cells. However, the detailed mechanism by which kaempferol alleviated ox-LDL-induced EC apoptosis remains largely elusive. METHODS: The expression of miR-26a-5p in human aortic endothelial cells (HAECs) treated with either ox-LDL alone or in combination with kaempferol was detected by qRT-PCR. Cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. The interaction between miR-26a-5p and toll-like receptor 4 (TLR4) mRNA was examined by luciferase reporter assay. The protein levels of TLR4, phosphorylated-p65, p65, phosphorylated-IκBα and IκBα were determined by western blot. RESULTS: Kaempferol upregulated miR-26a-5p expression in ox-LDL-stimulated HAECs. Moreover, kaempferol alleviated ox-LDL-induced apoptosis in HAECs by upregulating miR-26a-5p. Additionally, TLR4 mRNA was identified as a target of miR-26a-5p in ox-LDL-treated HAECs. TLR4 overexpression partially counteracted the anti-apoptotic role of miR-26a-5p in ox-LDL-treated HAECs. Furthermore, kaempferol inactivated the TLR4/nuclear factor kappa B (NF-κB) signaling pathway in ox-LDL-treated HAECs by upregulating miR-26a-5p. CONCLUSION: Kaempferol alleviated ox-LDL-induced apoptosis in HAECs by upregulating miR-26a-5p via inactivation of the TLR4/NF-κB signaling pathway, shedding light on the molecular mechanism by which kaempferol alleviated ox-LDL-induced EC apoptosis.

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS-mediated NLRP3 inflammasome activation.

NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti-hyperglycaemia and anti-inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL-1ß and IL-18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down-regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C-reactive proteins (CRPs), IL-1ß and IL-18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS-mediated NLRP3 inflammasome activation.

Downregulation of microRNA­34a inhibits oxidized low­density lipoprotein­induced apoptosis and oxidative stress in human umbilical vein endothelial cells.

Oxidized low­density lipoprotein (ox­LDL) promotes endothelial cell dysfunction, which is a primary risk factor for the development of atherosclerosis. A previous study reported that microRNA (miRNA/miR)­34a is upregulated in atherosclerotic samples. However, its function and underlying mechanisms remain to be fully elucidated. In the present study, miRNA microarray analysis was performed to investigate the miRNA expression profile in atherosclerotic plaque tissues and examine the role of miR­34a in ox­LDL­induced apoptosis of human umbilical vein endothelial cells (HUVECs). Cell viability, apoptosis and protein expression was determined by a cell counting kit­8 assay, flow cytometry and western blot analysis, respectively. It was observed that miR­34a was upregulated in atherosclerotic plaque tissues and that ox­LDL treatment significantly increased the levels of miR­34a in a dose­dependent manner in the HUVECs. The knockdown of miR­34a increased the protein expression of B­cell lymphoma 2 (Bcl­2) and cell viability, improved mitochondrial membrane potential, and decreased the activity of caspase­3, number of apoptotic cells and release of cytochrome c from mitochondria in the ox­LDL­treated HUVECs. The results also demonstrated that the knockdown of miR­34a suppressed the levels of ox­LDL­induced reactive oxygen species (ROS) in HUVECs. Additionally, it was found that Bcl­2 was a target of miR­34a in HUVECs, and that silencing Bcl­2 abrogated the protective effects of the downregulation of miR­34a on ox­LDL­induced apoptosis. These data indicated that the knockdown of miR­34a protected against ox­LDL apoptosis and ROS in HUVECs via inhibiting the mitochondrial apoptotic pathway, suggesting it may offer potential as a biomarker in the clinical diagnosis and as a target for the treatment of atherosclerosis.

Functional characterization of CXCR4 in mediating the expression of protein C system in experimental ulcerative colitis.

The present study aimed to explore the role of CXCR4 and protein C system (PCS) in the experimental ulcerative colitis (UC). The expression of CXCR3, CCR10, and CXCR4 in dextran sulfate sodium (DSS)-induced colitis mouse model was measured by immunohistochemistry and western blot analysis. In vitro studies with microvascular endothelial cells (MVECs) were performed. The expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) were detected by RT-PCR and western blot analysis. Activities of protein C (PC), protein S (PS), activated PC (APC) were evaluated in cells pre-treated with JNK inhibitor SP600125 and c-Jun silencing. DSS mice showed up-regulated expression of CXCR4, higher macroscopic score and histological score (P<0.05), as well as elevated levels of SDF-1α (P<0.05) compared with wild type, CXCR4-/-, or CXCR4-/- +DSS mice. In DSS mice, EPCR expression was down-regulated (P<0.05), accompanied by decreased activity of PC and PS (P<0.05 or P<0.01) with an up-regulated expression of pJNK MAPK and pc-Jun (P<0.05). Moreover, the macroscopic score and histological score index, SDF-1α levels, EPCR expression, PC activity, pJNK, and pc-Jun were reversed in CXCR4-/- +DSS mice (P<0.05). In vitro, SDF-1α-induced inhibition of the PCS was blunted by SP600125 (P<0.05). Meanwhile, down-regulation of c-Jun rescued the inhibition of PCS (P<0.05). MVECs with retrovirus-mediated transfection of c-Jun demonstrated a strong trans-inactivation effect on the EPCR promoter (P<0.05). These findings suggest that CXCR4 is involved in UC pathogenesis and could be a promising therapeutic target for UC treatment.

Double Kissing Crush Versus Provisional Stenting for Left Main Distal Bifurcation Lesions: DKCRUSH-V Randomized Trial.

BACKGROUND: Provisional stenting (PS) is the most common technique used to treat distal left main (LM) bifurcation lesions in patients with unprotected LM coronary artery disease undergoing percutaneous coronary intervention. The double kissing (DK) crush planned 2-stent technique has been shown to improve clinical outcomes in non-LM bifurcations compared with PS, and in LM bifurcations compared with culotte stenting, but has never been compared with PS in LM bifurcation lesions. OBJECTIVES: The authors sought to determine whether a planned DK crush 2-stent technique is superior to PS for patients with true distal LM bifurcation lesions. METHODS: The authors randomized 482 patients from 26 centers in 5 countries with true distal LM bifurcation lesions (Medina 1,1,1 or 0,1,1) to PS (n = 242) or DK crush stenting (n = 240). The primary endpoint was the 1-year composite rate of target lesion failure (TLF): cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Routine 13-month angiographic follow-up was scheduled after ascertainment of the primary endpoint. RESULTS: TLF within 1 year occurred in 26 patients (10.7%) assigned to PS, and in 12 patients (5.0%) assigned to DK crush (hazard ratio: 0.42; 95% confidence interval: 0.21 to 0.85; p = 0.02). Compared with PS, DK crush also resulted in lower rates of target vessel myocardial infarction I (2.9% vs. 0.4%; p = 0.03) and definite or probable stent thrombosis (3.3% vs. 0.4%; p = 0.02). Clinically driven target lesion revascularization (7.9% vs. 3.8%; p = 0.06) and angiographic restenosis within the LM complex (14.6% vs. 7.1%; p = 0.10) also tended to be less frequent with DK crush compared with PS. There was no significant difference in cardiac death between the groups. CONCLUSIONS: In the present multicenter randomized trial, percutaneous coronary intervention of true distal LM bifurcation lesions using a planned DK crush 2-stent strategy resulted in a lower rate of TLF at 1 year than a PS strategy. (Double Kissing and Double Crush Versus Provisional T Stenting Technique for the Treatment of Unprotected Distal Left Main True Bifurcation Lesions: A Randomized, International, Multi-Center Clinical Trial [DKCRUSH-V]; ChiCTR-TRC-11001213).

Inflammatory potential of diet and risk of cardiovascular disease or mortality: A meta-analysis.

Inconsistent findings have reported on the inflammatory potential of diet and cardiovascular disease (CVD) and mortality risk. The aim of this meta-analysis was to investigate the association between the inflammatory potential of diet as estimated by the dietary inflammatory index (DII) score and CVD or mortality risk in the general population. A comprehensive literature search was conducted in PubMed and Embase databases through February 2017. All prospective observational studies assessing the association of inflammatory potential of diet as estimated by the DII score with CVD and all-cause, cancer-related, cardiovascular mortality risk were included. Nine prospective studies enrolling 134,067 subjects were identified. Meta-analyses showed that individuals with the highest category of DII (maximal pro-inflammatory) was associated with increased risk of all-cause mortality (hazard risk [HR] 1.22; 95% confidence interval [CI] 1.06-1.41), cardiovascular mortality (RR 1.24; 95% CI 1.01-1.51), cancer-related mortality (RR 1.28; 95% CI 1.04-1.58), and CVD (RR 1.32; 95% CI 1.09-1.60) than the lowest DII score. More pro-inflammatory diets, as estimated by the higher DII score are independently associated with an increased risk of all-cause, cardiovascular, cancer-related mortality, and CVD in the general population, highlighting low inflammatory potential diet may reduce mortality and CVD risk.

Fortunellin protects against high fructose-induced diabetic heart injury in mice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation.

Inflammation and oxidative stress contribute to the progression of diabetic cardiomyopathy (DCM). The study was first designed to calculate the role of an anti-inflammatory and anti-oxidant Fortunellin (For) in high fructose-induced cardiac injury in diabetic mice. Fortunellin was found to be none of toxicity to mice and cells using various assays. High fructose was used to induce mice with diabetes. The heart histopathological changes and cardiac function were measured. Fortunellin significantly attenuated the score of histopathological alterations and alleviated heart function, accompanied with reduced inflammation and oxidative stress. The pro-inflammatory cytokines and the expression of p-IκB kinase α (IKKα), p-IκBα, and p-nuclear factor-κB (NF-κB) were dramatically reduced by Fortunellin, while superoxide dismutase (SOD), catalase (CAT), heme oxygenase-1 (HO-1) and p-AMP-activated protein kinase (AMPK) were significantly enhanced. Moreover, in H9C2 cells with nuclear factor erythroid 2-related factor 2 (Nrf2) knock-down abolished the prevention of Fortunellin against cardiac injury, proved by elevated inflammatory response and oxidative stress. Suppression of p-AMPK reduced the level of Nrf2 and HO-1 induced by Fortunellin, eliminating the protective role of Fortunellin. For the first time, our study suggested that Fortunellin protected against fructose-induced inflammation and oxidative stress by enhancing AMPK/Nrf2 pathway in diabetic mice and cardiomyocytes with fructose treatment.

Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis.

BACKGROUND AND AIMS: Inconsistent findings have been reported on the association between high-sensitivity C-reactive protein (hs-CRP) and mortality risk. The objective of this meta-analysis was to investigate the association of elevated baseline hs-CRP levels with all-cause, cardiovascular, and cancer mortality risk in the general population. METHODS: PubMed and Embase were systematically searched for studies published from inception to October 2016. Prospective observational studies were eligible if they reported the effects of elevated baseline hs-CRP levels on cancer-related, cardiovascular or all-cause mortality in the general population. The pooled adjusted risk ratio (RR) with 95% confidence interval (CI) comparing the highest to the lowest category of hs-CRP levels was used as association measures. RESULTS: A total of 83,995 participants from 14 studies were identified. When comparing the highest to the lowest category of hs-CRP levels, the pooled RR was 1.25 (95% CI 1.13-1.38) for cancer-related mortality, 2.03 (95% CI 1.65-2.50) for cardiovascular mortality, and 1.75 (1.55-1.98) for all-cause mortality, respectively. Subgroup analysis showed that the effect of elevated hs-CRP levels on cancer-related mortality was observed in men (RR 1.26; 95% CI 1.11-1.43) but not in women (RR 1.03; 95% CI 0.83-1.27). CONCLUSIONS: Elevated hs-CRP levels can independently predict risk of all-cause, cardiovascular mortality in the general population. However, the gender differences in the predictive role of hs-CRP on cancer mortality should to be further investigated.

Odanacatib Inhibits Resistin-induced Hypertrophic H9c2 Cardiomyoblast Cells Through LKB1/AMPK Pathway

ABSTRACT Odanacatib (ODN) is a selective inhibitor of cathepsin K. The cysteine protease cathepsin K has been implicated in cardiac hypertrophy. Resistine is an adipokine which is identified to promote cardiac hypertrophy. Here, we hypothesize that ODN mitigates resistin-induced myocyte hypertrophy. Cell surface area and protein synthesis were measured after treatment with resistin and ODN in H9c2 cells. The expression of cardiomyocyte hypertrophy marker BNP and β-MHC was detected by RT-qPCR. The expression and phosphorylation of AMPK and LKB1 were analyzed with Western blot. Resistin could significantly increase cardiomyocyte cell surface area, protein synthesis, and embryonic gene BNP and β-MHC expression, inhibit phosphorylation of AMPK and LKB1. ODN could significantly reverse the effects of resistin. Collectively, our data suggest that ODN can inhibit cardiomyocyte hypertrophy induced by resistin and the underlying mechanism may be involved in LKB1/AMPK pathway.

Resistin-induced cardiomyocyte hypertrophy is inhibited by apelin through the inactivation of extracellular signal-regulated kinase signaling pathway in H9c2 embryonic rat cardiomyocytes.

It has been reported that resistin induces, whereas apelin inhibits cardiac hypertrophy. However, the underlying molecular mechanisms of apelin inhibiting resistin-induced cardiac hypertrophy remain unclear. The aim of the current study is to investigate the effects of apelin on resistin-induced cardiomyocyte hypertrophy and elucidate the underlying molecular mechanism. H9c2 cells were used in the present study, and cell surface area and protein synthesis were evaluated. Reverse transcription-quantitative polymerase chain reaction was performed to analyze the expression levels of hypertrophic markers, brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC). In addition, western blotting was conducted to examine phosphorylation of extracellular signal-regulated kinase (ERK)1/2. Following treatment of H9c2 cells with resistin, cell surface area, protein synthesis, and BNP and ß-MHC mRNA expression levels were increased. Subsequent to co-treatment of H9c2 cells with apelin and resistin, lead to the inhibition of resistin-induced hypertrophic effects by apelin. In addition, treatment with resistin increased phosphorylation of ERK1/2, whereas pretreatment with apelin decreased phosphorylation of ERK1/2, which was increased by resistin. These results indicate that resistin-induced cardiac hypertrophy is inhibited by apelin via inactivation of ERK1/2 cell signaling.

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes.

Resistin has been previously demonstrated to induce cardiac hypertrophy, however, the underlying molecular mechanisms of resistin-induced cardiac hypertrophy remain unclear. Using H9c2 cells, the present study investigated the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway for a potential role in mediating resistin-induced cardiomyocyte hypertrophy. Treatment of H9c2 cells with resistin increased cell surface area, protein synthesis, and expression of hypertrophic marker brain natriuretic peptide and ß-myosin heavy chain. Treatment with metformine attenuated these effects of resistin. Furthermore, treatment with resistin decreased phosphorylation of LKB1 and AMPK, whereas pretreatment with metformin increased phosphorylation of LKB1 and AMPK that is reduced by resistin. These results suggest that resistin induces cardiac hypertrophy through the inactivation of the LKB1/AMPK cell signaling pathway.