Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Mechanism of balloon burst during transcatheter aortic valve replacement pre-dilatation: Image observation and validation by finite element analysis.

BACKGROUND: Balloon burst during transcatheter aortic valve replacement (TAVR) is serious complication. This study pioneers a novel approach by combining image observation and computer simulation validation to unravel the mechanism of balloon burst in a patient with bicuspid aortic valve (BAV) stenosis. METHOD: A new computational model for balloon pre-dilatation was developed by incorporating the element failure criteria according to the Law of Laplace. The effects of calcification and aortic tissue material parameters, friction coefficients, balloon types and aortic anatomy classification were performed to validate and compare the expansion behavior and rupture mode of actual balloon. RESULTS: Balloon burst was dissected into three distinct stages based on observable morphological changes. The mechanism leading to the complete transverse burst of the non-compliant balloon initiated at the folding edges, where contacted with heavily calcified masses at the right coronary sinus, resulting in high maximum principal stress. Local sharp spiked calcifications facilitated rapid crack propagation. The elastic moduli of calcification significantly influenced balloon expansion behavior and crack morphology. The simulation case of the calcific elastic modulus was set at 12.6 MPa could closely mirror clinical appearance of expansion behavior and crack pattern. Furthermore, the case of semi-compliant balloons introduced an alternative rupture mechanism as pinhole rupture, driven by local sharp spiked calcifications. CONCLUSIONS: The computational model of virtual balloons could effectively simulate balloon dilation behavior and burst mode during TAVR pre-dilation. Further research with a larger cohort is needed to investigate the balloon morphology during pre-dilation by using this method to guide prosthesis sizing for potential favorable outcomes.

Loss of USP22 alleviates cardiac hypertrophy induced by pressure overload through HiF1-α-TAK1 signaling pathway.

Ubiquitin-specific protease 22 (USP22) is a member of the ubiquitin specific protease family (ubiquitin-specific protease, USPs), the largest subfamily of deubiquitinating enzymes, and plays an important role in the treatment of tumors. USP22 is also expressed in the heart. However, the role of USP22 in heart disease remains unclear. In this study, we found that USP22 was elevated in hypertrophic mouse hearts and in angiotensin II (Ang II)-induced cardiomyocytes. The inhibition of USP22 expression with adenovirus significantly rescued hypertrophic phenotype and cardiac dysfunction induced by pressure overloaded. Consistent with in vivo study, silencing by USP22 shRNA expression in vitro had similar results. Molecular analysis revealed that transforming growth factor-ß-activating protein 1 (TAK1)-(JNK1/2)/P38 signaling pathway and HIF-1α was activated in the Ang II-induced hypertrophic cardiomyocytes, whereas HIF-1α expression was decreased after the inhibition of USP22. Inhibition of HIF-1α expression reduces TAK1 expression. Co-immunoprecipitation and ubiquitination studies revealed the regulatory mechanism between USP22 and HIF1α.Under hypertrophic stress conditions, USP22 enhances the stability of HIF-1α through its deubiquitination activity, which further activates the TAK1-(JNK1/2)/P38 signaling pathway to lead to cardiac hypertrophy. Inhibition of HIF-1α expression further potentiates the in vivo pathological effects caused by USP22 deficiency. In summary, this study suggests that USP22, through HIF-1α-TAK1-(JNK1/2)/P38 signaling pathway, may be potential targets for inhibiting pathological cardiac hypertrophy induced by pressure overload.

Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling.

Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

Cardiac-Specific Overexpression of Caveolin-1 in Rats With Ischemic Cardiomyopathy Improves Arrhythmogenicity and Cardiac Remodelling.

BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter. RESULTS: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-ß (TGF-ß)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels. CONCLUSIONS: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.

Plasma Cell-Free DNA as a Novel Biomarker for the Diagnosis and Monitoring of Atherosclerosis.

Atherosclerosis (AS) is the leading cause of cardiovascular diseases (CVDs) with a high rate of mortality worldwide. Plasma cell-free DNA (cfDNA), mainly originating from apoptosis, necrosis, and active secretion, has been recognized as a promising biomarker for the diagnosis and prognosis of multiple cancers, whereas there are no reports about cfDNA in CVDs. Here, we found an increased quantity and decreased integrity of cfDNA (cfDI) in the serum from AS patients compared with normal controls. Moreover, the reduced cfDI is inversely correlated with serum LDL levels, carotid plaque size, and carotid plaque thickness in the progression of AS. Consistently, in vivo experiments confirmed that the release and cleavage of cfDNA were increased concomitantly with the development and progression of AS in ApoE-/- mice. Our study sheds light on the potential of cfDNA and cfDI as molecular biomarkers for detecting and monitoring AS.

Ferroptosis Associates With Diagnosis and Prognosis by Promoting Antitumor Immune Response in Melanoma.

Immunotherapy has greatly improved the clinical benefits of cancer treatment, especially in melanoma. Ferroptosis is a novel mechanism of cell death which relates to immunity. This study aimed at understanding the potential link between ferroptosis and cancer immunocompetent in melanoma using multiple bioinformatics analyses. By the WGCNA assay, we first constructed a key module-gene of ferroptosis, which was strongly correlated with the diagnosis, prognosis, and infiltration of immune cells in melanoma. The elevated module-gene could effectively distinguish melanoma from normal tissues and acted as a good prognostic marker. The module-gene of ferroptosis was positively correlated with the infiltration of immune cells. In particular, the module was positively correlated with the expression of PD-L1 and sensitively increased after effective anti-PD-1 treatment. Furthermore, the differential expression of the module-gene between normal and tumor tissues was observed in pan-cancer. The similarity correlations of the module-gene with infiltration of immune cells and the expressions of PD-L1 were confirmed in the pan-cancer level. Our study demonstrated that the key module-gene of ferroptosis was closely related with diagnosis, prognosis, and anti-immune response in melanoma, as well as in pan-cancer.

Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K/AKT Pathway in Mice.

Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury. In vitro, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI model in vivo and in vitro. The use of the specific PI3K/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K/AKT signaling pathway.

Inhibition of TGFß-activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression.

Transforming growth factor ß-activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z-7-oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R-induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R-induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.

Dexmedetomidine Exerted Anti-arrhythmic Effects in Rat With Ischemic Cardiomyopathy via Upregulation of Connexin 43 and Reduction of Fibrosis and Inflammation.

BACKGROUND: Persistent myocardial ischemia post-myocardial infarction can lead to fatal ventricular arrhythmias such as ventricular tachycardia and fibrillation, both of which carry high mortality rates. Dexmedetomidine (Dex) is a highly selective α2-agonist used in surgery for congenital cardiac disease because of its antiarrhythmic properties. Dex has previously been reported to prevent or terminate various arrhythmias. The purpose of the present study was to determine the anti-arrhythmic properties of Dex in the context of ischemic cardiomyopathy (ICM) after myocardial infarction. METHODS AND RESULTS: We randomly allocated 48 rats with ICM, created by persistent ligation of the left anterior descending artery for 4 weeks, into six groups: Sham (n = 8), Sham + BML (n = 8), ICM (n = 8), ICM + BML (n = 8), ICM + Dex (n = 8), and ICM + Dex + BML (n = 8). Treatments started after ICM was confirmed (the day after echocardiographic measurement) and continued for 4 weeks (inject intraperitoneally, daily). Dex inhibited the generation of collagens, cytokines, and other inflammatory mediators in rats with ICM via the suppression of NF-κB activation and increased the distribution of connexin 43 (Cx43) via phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Dex reduced the occurrence of spontaneous ventricular arrhythmias (ventricular premature beat or ventricular tachycardia), decreased the inducibility quotient of ventricular arrhythmias induced by PES, and partly improved cardiac contraction. The AMPK antagonist BML-275 dihydrochloride (BML) partly weakened the cardioprotective effect of Dex. CONCLUSION: Dex conferred anti-arrhythmic effects in the context of ICM via upregulation of Cx43 and suppression of inflammation and fibrosis. The anti-arrhythmic and anti-inflammatory properties of Dex may be mediated by phosphorylation of AMPK and subsequent suppression of NF-κB activation.

Label-free detection of biomarker alpha fetoprotein in serum by ssDNA aptamer functionalized magnetic nanoparticles.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the clinic, with the characteristics of occult onset, rapid progression, and high degree of malignancy. Alpha fetoprotein (AFP) is the most important biomarker of HCC, which is widely used in early screening, diagnosis, and prognosis observation. A series of immunoassays have been developed and frequently used in the detection of AFP based on antibodies. Unfortunately, the shortcomings of antibodies, such as thermal unstable and fluctuant activity by batches, lead to the inaccuracy in the detection of AFP. In this study, aptamers instead of antibodies were adopted as the specific recognition element for AFP, aiming to seek an alternative strategy to immunoassays. An AFP-specific ssDNA aptamer was grafted to magnetic nanoparticles (Fe3O4@SiO2) via avidin-biotin interaction, and the resultant aptamer functionalized magnetic nanoparticles (Ap-MNPs) were adequately characterized and tested. The Ap-MNPs in solution exhibited a fast response to the outer magnetic field, and can be completely separated in several minutes. It was found that Ap-MNPs have good specificity to the target AFP, as the recovery of AFP (87.0%) was much higher than the competitive proteins IgG (38.9%), HSA (18.5%), and FIB (11.4%). A convenient and efficient label-free detection method of AFP in serum was developed based on Ap-MNPs in combination with high-performance liquid chromatography. The linearity of this method was over a range of 1-50 µg ml-1 with a correlation coefficient of 0.9999, and the limit of detection was 0.27 µg ml-1. This study indicated that aptamers are an ideal tool for the recognition and detection of biomarkers, and thus will find wide applications in clinical practice.

Association of N6-methyladenine DNA with plaque progression in atherosclerosis via myocardial infarction-associated transcripts.

Modification of the novel N6-methyladenine (m6A) DNA implicates this epigenetic mark in human malignant disease, but its role in atherosclerosis (AS) is largely unknown. Here, we found that the leukocyte level of m6A but not 5mC DNA modification was decreased with increasing of carotid plaque size and thickness in 207 AS patients as compared with 142 sex- and age-matched controls. Serum low-density lipoprotein (LDL) and leukocyte m6A levels were associated with the progression of carotid plaque size and thickness. Both LDL level and plaque thickness were also independently and negatively related to m6A level. Reduced m6A level was further confirmed in leukocytes and endothelium in western diet-induced AS mice and in oxidized-LDL (ox-LDL)-treated human endothelium and monocyte cells. Decreased m6A level was closely related to the upregulation of AlkB homolog 1 (ALKBH1), the demethylase of m6A. Silencing of ALKBH1 or hypoxia-inducible factor 1α (HIF1α) could rescue the ox-LDL-increased level of MIAT, a hypoxia-response gene. Mechanically, ox-LDL induced HIF1α for transfer into the nucleus. Nuclear HIF1α bound to the ALKBH1-demethylated MIAT promoter and transcriptionally upregulated its expression. Therefore, elevated ALKBH1 level in endothelium and leukocytes reduced m6A level, which is a novel and sensitive biomarker for AS progression.

Changes of N6-methyladenosine modulators promote breast cancer progression.

BACKGROUND: Breast cancer (BC) displays striking genetic, epigenetic and phenotypic diversity. N6-methyladenosine (m6A) in mRNA has emerged as a crucial epitranscriptomic modification that controls cancer self-renewal and cell fate. However, the key enzymes of m6A expression and function in human breast carcinogenesis remain unclear. METHODS: The expression of m6A methylases (METTL3, METTL14 and WTAP) and demethylases (FTO and ALKBH5) were analyzed by using ONCOMINE and The Cancer Genome Atlas databases and in 36 pairs of BC and adjacent non-cancerous tissue. The level of m6A in BC patients was detected by ELISA, and the function of m6A was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and transwell assay. The database of bc-GenExMiner v4.0, Kaplan-Meier Plotter and cBioPortal were queried for correlation, mutation and prognosis analysis of BC. RESULTS: The m6A methylases and demethylases were dysregulated in several major malignant tumors. Specifically, the expression of all m6A methylases was reduced in BC as compared with normal controls, but the demethylase ALKBH5 was induced in ONCOMINE databases and confirmed in clinical patients. METTL14 expression was positively correlated with METTL3 expression, and both showed high expression in normal breast-like and luminal-A and -B BC. Functionally, reducing m6A expression by overexpressing METTL14 and/or knockdown of ALKBH5 could inhibit breast cell viability, colony formation and cell migration. Furthermore, Kaplan-Meier, meta-analysis and univariate Cox assay showed that the expression of m6A members including METTL3, METTL14, WTAP and FTO but not their gene mutation and amplification, was tightly associated with cancer progression and poor survival. CONCLUSIONS: Changes of m6A modulators reduced m6A may promote tumorigenesis and predict poor prognosis in BC.

Loss of FOXP3 and TSC1 Accelerates Prostate Cancer Progression through Synergistic Transcriptional and Posttranslational Regulation of c-MYC.

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells. SIGNIFICANCE: These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1413/F1.large.jpg.

FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis.

BACKGROUND: FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC). METHODS: Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay. FINDINGS: Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan-Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca2+ cytosol influx from ER and extracellular, as well as NFATC1 nuclear translocation and activity. Nuclear NFATC1 bound to the BMI1 gene promoter and transcriptionally upregulated its expression. Notably, BMI1 overexpression could rescue the loss of function of FUNDC1. Co-expression of FUNDC1 and BMI1 in BC patients predicted worse prognosis than without either expression. INTERPRETATION: FUNDC1 might promote BC progression by activating the Ca2+-NFATC1-BMI1 axis. This pathway may be promising for developing multiple targets for BC therapy.

Loss of P53 regresses cardiac remodeling induced by pressure overload partially through inhibiting HIF1α signaling in mice.

The tumor suppressor p53 is recognized as the guardian of the genome in cell cycle and cell death. P53 expression increases as cardiac hypertrophy worsens to heart failure, suggesting that p53 may play important role in cardiac remodeling. In the present study, deletion of p53 in the mice heart would ameliorate cardiac hypertrophy induced by pressure overload. The role of p53 on heart was investigated using in vivo models. Cardiac hypertrophy in mice was induced by transverse aortic banding surgery. The extent of cardiac hypertrophy was examined by echocardiography, as well as pathological and molecular analyses of heart tissue. Global knockout of p53 in the mice reduced the hypertrophic response and markedly reduced cardiac apoptosis, and fibrosis. Ejection fraction of heart was also improved in hearts without p53 in response to pressure overload. Protein determination further suggested loss of p53 expression markedly increased Hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) expression. The study indicated p53 deteriorated cardiac functions and cardiac hypertrophy, apoptosis, and fibrosis by partially inhibition of HIF1α and VEGF.

Ellagic acid promotes ventricular remodeling after acute myocardial infarction by up-regulating miR-140-3p.

In the paper, we observed the effect of ellagic acid (EA) on myocardial morphology and cardiac function and explored the mechanism of miR-140-3p-mediated EA in ventricular remodeling. The experimental animals were divided into 3 groups: control group, AMI group, AMI+EA group. Intragastric administration for 4 weeks was initiated on the first day after surgery in rats. Rodent echocardiography was used to measure heart size and cardiac function. The level of fibrosis was observed by Masson staining. The number of cell apoptosis was detected by TUNEL method. The expression of miR-140-3p and MKK6 was measured by qRT-PCR and Western blot, respectively. The results showed that EA could effectively improve the left ventricular function of AMI rats, reduce fibrosis area and infarct area. Moreover, EA significantly increased the expression of miR-140-3p and inhibited the expression of MKK6. However, miR-140-3p inhibitor up-regulated MKK6 expression, and miR-140-3p overexpression reversed the expression. In addition, EA could inhibit cell apoptosis, while miR-140-3p inhibitor increased cell apoptosis. After transfection with si-MKK6, the level of cell apoptosis was significantly decreased. These results indicated that EA improved ventricular remodeling after myocardial infarction by up-regulating miR-140-3p expression and inhibiting MKK6 expression.

Loss of TRADD attenuates pressure overload-induced cardiac hypertrophy through regulating TAK1/P38 MAPK signalling in mice.

We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice.

Olmesartan ameliorates pressure overload-induced cardiac remodeling through inhibition of TAK1/p38 signaling in mice.

AIMS: Many studies have demonstrated the potent effects of ARB administration on heart failure. However, the mechanism of the potent effects of ARB on cardiac remodeling is less well understood. We investigated the role of Olmesartan on the fibrosis and hypertrophy in mouse heart. MATERIALS AND METHODS: We employed TAC surgery, a mouse model of chronic cardiac failure. All the mice were separated into three groups: the sham group, TAC group and TAC plus Olmesartan group (given Olmesartan treatment after TAC). We analyzed left ventricle remodeling, and function by echocardiography or pathology. We further detected the level of marker genes involved in fibrosis and hypertrophy and in cultured neonatal rat cardiac fibroblasts and myocytes infected by constitutively active TAK1 and p38MAPK. After TAC, all the mice developed hypertrophy, worse cardiac function and malignant remodeling in left ventricle. KEY FINDINGS: Olmesartan improved heart remodeling and function without changing pressure of blood. Moreover, Olmesartan reduced the level of transforming growth factor ß activated kinase-1 (TAK1) and phospho-p38MAPK. In neonatal rat cardiac fibroblast cells and cardiomyocytes, Olmesartan also decreased TAK1 and p38MAPK activation triggered by TGFß1 or AngII. The inhibitory effect of Olmesartan was abrogated by overexpression of constitutively active TAK1 and p38MAPK by adenovirus system. SIGNIFICANCE: Our results suggest Olmesartan improves heart remodeling and function induced by pressure overload. P38MAPK inactivation attenuated by olmesartan via inhibition of TAK1 pathway plays an important role in the process.

Increased cardiac remodeling in cardiac-specific Flt-1 receptor knockout mice with pressure overload.

Vascular endothelial growth factor (VEGF) inhibition has previously been shown to have damaging effects on the heart. Because the role of Flt-1 (a phosphotyrosine kinase receptor for VEGF) in cardiac function and hypertrophy is unclear, we generated mice lacking Flt-1 only in their cardiomyocytes (Flt-1 KO). The hearts from 8- to 10-week-old mice were measured by using echocardiography and histology. No significant differences were seen in fraction shortening, cross-sectional area of cardiomyocytes, and interstitial collagen fraction between littermate controls and KO mice at baseline. To test the hypothesis that Flt-1 is involved in cardiac remodeling, we performed transverse aorta constriction (TAC) by ligating the transverse ascending aorta. Four weeks after TAC, echocardiography of the mice was performed, and the hearts were excised for pathological analysis and Western blotting. No difference in mortality was found between Flt-1 KO mice and controls; however, KO mice showed a greater cardiomyocyte cross-sectional area and interstitial collagen fraction than controls. Western blotting indicated that AKT was activated less in Flt-1 KO hearts after TAC compared with that in control hearts. Thus, Flt-1 deletion in cardiomyocytes increased hypertrophy, fibrosis, and regression of AKT phosphorylation. Our study suggests that Flt-1 plays a critical role in cardiac hypertrophy induced by pressure overload via the activation of AKT, which seems to be cardioprotective.