Cardiac-specific deletion of heat shock protein 60 induces mitochondrial stress and disrupts heart development in mice.

Congenital heart diseases are the most common birth defects around the world. Emerging evidence suggests that mitochondrial homeostasis is required for normal heart development. In mitochondria, a series of molecular chaperones including heat shock protein 60 (HSP60) are engaged in assisting the import and folding of mitochondrial proteins. However, it remains largely obscure whether and how these mitochondrial chaperones regulate cardiac development. Here, we generated a cardiac-specific Hspd1 deletion mouse model by αMHC-Cre and investigated the role of HSP60 in cardiac development. We observed that deletion of HSP60 in embryonic cardiomyocytes resulted in abnormal heart development and embryonic lethality, characterized by reduced cardiac cell proliferation and thinner ventricular walls, highlighting an essential role of cardiac HSP60 in embryonic heart development and survival. Our results also demonstrated that HSP60 deficiency caused significant downregulation of mitochondrial ETC subunits and induced mitochondrial stress. Analysis of gene expression revealed that P21 that negatively regulates cell proliferation is significantly upregulated in HSP60 knockout hearts. Moreover, HSP60 deficiency induced activation of eIF2α-ATF4 pathway, further indicating the underlying mitochondrial stress in cardiomyocytes after HSP60 deletion. Taken together, our study demonstrated that regular function of mitochondrial chaperones is pivotal for maintaining normal mitochondrial homeostasis and embryonic heart development.

IL-17A-induced cancer-associated fibroblasts releases CXCL12 to promote lung adenocarcinoma progression via Wnt/ß-Catenin signaling pathway.

BACKGROUND: Cancer-associated fibroblasts (CAFs) and their secretion, C-X-C motif chemokine ligand 12 (CXCL12), play an important role in the development of lung adenocarcinoma (LUAD). Interleukin 17A (IL-17A) is also crucial in regulating tumor progression. Herein, we explored the specific relationships between these two factors and their mechanisms in the progression of LUAD. METHODS: Immunohistochemistry was utilized to assess the differential expression levels of IL-17A and CXCL12 in tumor versus normal tissues of LUAD patients, followed by gene correlation analysis. Cell counting kit-8 (CCK8), wound-healing and transwell assays were performed to investigate the effect of IL-17A on the function of LUAD cells. qPCR, immunofluorescence, immunohistochemistry and western blot analyses were conducted to elucidate the potential mechanism by which IL-17A facilitates the development of LUAD via CXCL12. Male BALB-C nude mice were used to explore the role of IL-17A in subcutaneous LUAD mouse models. RESULTS: Elevated expression levels of IL-17A and CXCL12 were observed in LUAD tissues, exhibiting a positive correlation. Further studies revealed that IL-17A could stimulate CAFs to enhance the release of CXCL12, thereby facilitating the growth, proliferation, and metastasis of LUAD. The binding of CXCL12 to its specific receptor influences the activation of the Wnt/ß-Catenin pathway, which in turn affects the progression of LUAD. In vivo experiments have demonstrated that IL-17A enhances the growth of LUAD tumors by facilitating the secretion of CXCL12. Conversely, inhibiting CXCL12 has been demonstrated to impede tumor growth. CONCLUSIONS: We discovered that IL-17A promotes the release of CAFs-derived CXCL12, which in turn facilitates the development of LUAD via the Wnt/ß-Catenin signaling pathway.

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection.

Aortic dissection (AD) is a fatal cardiovascular disease with limited pharmacotherapies. To discover novel therapeutic targets for AD, the present study was conducted on ascending aorta samples from AD patients versus those from control subjects using proteomic analysis. Integrated proteomic data analysis identified S100 calcium-binding proteins A8 and A9 (S100A8/A9) as new therapeutic targets for AD. As assessed by ELISA, the circulating levels of S100A8/A9 were elevated in AD patients. In addition, we validated the upregulation of S100A8/A9 in a mouse model of AD. In vitro and in vivo studies substantiated that S100A8/A9, as danger-associated molecular pattern molecules, promotes the smooth muscle cells phenotypic switch by inhibiting serum response factor (SRF) activity but elevating NF-κB dependent inflammatory response. Depletion of S100A8/A9 attenuates the occurrence and development of AD. As a proof of concept, we tested the safety and efficacy of pharmacological inhibition of S100A8/A9 by ABR-25757 (paquinimod) in a mouse model of AD. We observed that ABR-25757 ameliorated the incidence of rupture and improved elastin morphology associated with AD. Further single-cell RNA sequencing disclosed that the phenotypic switch of vascular smooth muscle cells (VSMCs) and inflammatory response pathways were responsible for ABR-25757-mediated protection against AD. Thus, this study reveals the regulatory mechanism of S100A8/A9 in AD and offers a potential therapeutic avenue to treat AD by targeting S100A8/A9.

Exosomes from umbilical cord-derived mesenchymal stem cells combined with gelatin methacryloyl inhibit vein graft restenosis by enhancing endothelial functions.

BACKGROUND: The prevalence of coronary artery disease is increasing. As a common treatment method, coronary artery bypass transplantation surgery can improve heart problems while also causing corresponding complications. Venous graft restenosis is one of the most critical and intractable complications. Stem cell-derived exosomes could have therapeutic promise and value. However, as exosomes alone are prone to inactivation and easy removal, this therapeutic method has not been widely used in clinical practice. Methacrylated gelatin (GelMA) is a polymer with a loose porous structure that maintains the biological activity of the exosome and can control its slow release in vivo. In this study, we combined human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) and GelMA to explore their effects and underlying mechanisms in inhibiting venous graft restenosis. RESULTS: Human umbilical cord mesenchymal stem cells (hUCMSCs) were appraised using flow cytometry. hUCMSC-Exos were evaluated via transmission electron microscopy and western blotting. hUCMSC-Exos embedded in a photosensitive GelMA hydrogel (GelMA-Exos) were applied topically around venous grafts in a rat model of cervical arteriovenous transplantation, and their effects on graft reendothelialization and restenosis were evaluated through ultrasonic, histological, and immunofluorescence examinations. Additionally, we analyzed the material properties, cellular reactions, and biocompatibility of the hydrogels. We further demonstrated that the topical application of GelMA-Exos could accelerate reendothelialization after autologous vein transplantation and reduce restenosis in the rat model. Notably, GelMA-Exos caused neither damage to major organs in mice nor excessive immune rejection. The uptake of GelMA-Exos by endothelial cells stimulated cell proliferation and migration in vitro. A bioinformatic analysis of existing databases revealed that various cell proliferation and apoptosis pathways, including the mammalian target of rapamycin (mTOR)-phosphoinositide 3-kinase (PI3K)-AKT signaling pathways, might participate in the underlying regulatory mechanism. CONCLUSIONS: Compared with the tail vein injection of hUCMSC-Exos, the local application of a mixture of hUCMSC-Exos and GelMA was more effective in promoting endothelial repair of the vein graft and inhibiting restenosis. Therefore, the proposed biomaterial-based therapeutic approach is a promising treatment for venous graft restenosis.

Association of Globodera rostochiensis (Nematoda) with Stunted and Chlorotic Potato Plants in Yunnan and Sichuan Provinces in China.

On a global basis, potato cyst nematodes (Globodera spp. Skarbilovich 1959 [Behrens 1975]) are one of the most serious soilborne pathogens in potato (Solanum tuberosum L.) production. In 2019 to 2020, 188 soil samples were taken from rhizosphere soil associated with the roots of stunted and chlorotic potato plants in the main potato-growing areas of Yunnan and Sichuan Provinces of China. Globodera rostochiensis Wollenweber 1923 (Skarbilovich 1959) was recovered from 112 of the samples. Nematode identification was as confirmed by morphometric, light microscopy, electron microscopy, and molecular methodologies. Population densities of G. rostochiensis ranged from 47.0 to 69.0 eggs/g of soil. A BLASTn homology search program was used to compare the sequences of populations of G. rostrochienses from Yunnan and Sichuan Provinces with populations of other Heteroderinae spp. and populations of G. rostochiensis from other nations. Although potato has been grown in China for at least 400 years and the nation produces more potato than any other country, potato cyst nematodes were not reported in China until 2022.

A Case of Giant Left Circumflex Coronary Fistula Aneurysm with Unidentified Fistula.

A coronary aneurysm is a rare type of cardiovascular disease. We report a case of a 53-year-old male patient who presented to our hospital with a giant left circumflex coronary fistula aneurysm (LCCA) (75 mm × 70 mm). Since coronary angiography and coronary computed tomography angiography failed to detect the fistula of the coronary aneurysm, interventional occlusion surgery could not be performed. We discovered the fistula in the right atrium by anterograde perfusion with blood-containing myocardial protective fluid after switching to intraoperative exploration during cardiac surgery. The coronary aneurysm's fistula and inlet were then sutured, and the aneurysm was resected. The patient recovered successfully after the operation. This case was instructive in managing LCCA, especially with an unidentified fistula.

Mechanism of CREB1 in cardiac function of rats with heart failure via regulating the microRNA-376a-3p/TRAF6 axis.

Heart failure (HF) is a complicated disease resulting from impaired heart function. CREB1 is a candidate target in heart-concerning diseases. This paper attempts to explore the role of CREB1 in HF. Initially, the HF rat model was established by constricted abdominal aortic surgery and the cardiac function of HF rats was assessed by ultrasonic cardiogram. Levels of CK-MB and LDH and activity of Caspase-3 and Caspase-9 in HF rats were determined. Subsequently, myocardium pathological injury and myocardium apoptosis were detected. Additionally, the interactions between CREB1 and miR-376a-3p and between miR-376a-3p and TRAF6 were verified. The roles of CREB1, miR-376a-3p, and TRAF6 in HF were evaluated. In HF rats, CREB1 and miR-376a-3p were both downregulated while TRAF6 was upregulated. Besides, HF rats had decreased values of EF and FS, elevated levels of CK-MB and LDH, inflammatory infiltration, promoted cardiomyocyte apoptosis, and elevated activity of Caspase-3 and Caspase-9, which were all reversed by CREB1. Additionally, CREB1 activated miR-376a-3p expression, and miR-376a-3p targeted TRAF6 transcription. Both miR-376a-3p knockdown and TRAF6 overexpression annulled the protective role of CREB1 overexpression in cardiac function of HF rats. CREB1 activated miR-376a-3p expression to suppress TRAF6, thereby promoting the cardiac function of HF rats.

Atorvastatin Exerts Protective Effect on Cardiopulmonary Bypass Induced Renal Injury in Rats via PPAR-γ.

BACKGROUND: To investigate the protective effect and possible mechanism of atorvastatin pretreatment on renal function after cardiopulmonary bypass (CPB) in rats. METHODS: Twenty-four adult male Sprague-Dawley (SD) rats randomly were divided into three groups: Sham operation group, CPB group, and administration group (N = 8 in each group). The caudal artery and right jugular vein were used to establish the CPB circuit for the CPB and administration groups. Drugs were administered by oral gavage one week before the operation. All rats were executed for succeeding experiments 72h after the operation. Plasma levels of creatinine (Cre) and IL-8 at different time points and levels of TNF-α and MPO in renal tissue were detected by ELISA. Renal pathological changes were observed by HE staining. PPAR-γ expression was determined by immunohistochemistry and western blot. RESULTS: All rats survived the whole process without incident. Renal function of rats undergoing CPB was impaired to varying degrees based on the plasma Cre concentration, and atorvastatin pretreatment alleviated this effect. The concentrations of six inflammatory cytokines (IL-1ß, IL-6,IL-8, IFN-γ,TNF-α, and MPO) were significantly elevated after CPB procedure, while atorvastatin pretreatment ameliorated the inflammatory condition caused by CPB. Further analysis showed that in both HK-2 cells and renal tissues, atorvastatin promoted the expression of PPAR-γ. CONCLUSION: Atorvastatin pretreatment exerted protective effect on CPB-associated kidney injury and inflammation in rats. The activation of PPAR-γ may contribute to the protective effect of Atorvastatin.

The Impact of Diabetes on Acute Kidney Injury After Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: Acute kidney injury (AKI) is one of the most frequent complications after coronary artery bypass grafting. Previous studies have shown that diabetes is a key pathogenic factor. But how diabetes is related to AKI in off-pump CABG patients still is in debate. Here, we aim to study the relationship between diabetes and AKI after off-pump coronary artery bypass grafting (off-pump CABG). METHODS: Patients who underwent off-pump CABG from April 2017 to December 2020 in The First Affiliated Hospital of USTC were enrolled in this retrospective study. AKI was defined and classified, according to the criteria proposed by the Acute Kidney Injury Network. The incidence risk of acute kidney injury was measured by logistic regression and compared. RESULTS: A total of 395 patients, who underwent off-pump CABG, were included in this study. The postoperative acute kidney injury rate for a patient with diabetes was significantly higher than for patients without diabetes (x2 = 5.09, P = 0.024). Logistic regression analysis showed that patients with diabetes have a much higher risk with acute kidney injury occurring after off-pump coronary artery bypass grafting (OR 1.852, 95% CI 1.161 - 2.954, P = 0.01). CONCLUSIONS: Diabetes is an independent risk factor for postoperative AKI for patients undergoing off-pump CABG.

A Case of Giant Right Atrium Diverticulum with Atrial Septal Defect.

Right atrium diverticulum is a rare congenital malformation. We present a previously unreported case of giant right atrium diverticulum (153 × 109 mm) in a 17-year-old female patient. Echocardiographic examination also showed an atrial septal defect (11 mm). Considering the risk of right atrium rupture, we performed femoral arteriovenous cannulation first, followed by median thoracotomy. The defect was repaired with an autologous pericardial patch. The patient recovered well after the operation, and this case is referential for surgical treatment of giant right atrium diverticulum.

BIRC5, GAJ5, and lncRNA NPHP3-AS1 Are Correlated with the Development of Atrial Fibrillation-Valvular Heart Disease.

The aim of this study was to explore the pivotal genes or lncRNAs involved in the progression of atrial fibrillation (AF) -valvular heart disease (VHD). The mRNA profiling GSE113013 was obtained from the Gene Expression Omnibus database. The identification of differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs) was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out for DEGs. Then, the construction of the protein-protein interaction (PPI) network was conducted. An lncRNA-miRNA-target ceRNA network was constructed after obtaining microRNAs (miRNA) related to DElncRNAs. Ultimately, key disease-related genes were screened. A total of 399 DEGs and 145 DElncRNAs were obtained. There were 283 nodes and 588 interaction pairs in the PPI network, and synaptosome-associated protein 25 (SNAP25) had higher degrees (degree = 22) in the PPI network. There were 65 interaction pairs in the ceRNA network. Here, Baculoviral IAP Repeat Containing 5 (BIRC5) was regulated by hsa-miR-1285-3p, which was regulated by lncRNA NPHP3-AS1. Gap Junction Protein Alpha 5 (GAJ5) was regulated by hsa-miR-4505, hsa-miR-1972, and hsa-miR-1199-5p. In particular, GAJ5 was enriched in the function of ion transmembrane transport regulation, whereas BIRC5 was enriched in the function of apoptosis-multiple species pathway. Similarly, Potassium Inwardly Rectifying Channel Subfamily J Member 6 (KCNJ6) was enriched in the function of an ion channel complex. VENN analysis identified BIRC5 and GJA5 as key AF-related genes. KCNJ6, SNAP25, GJA5, BIRC5, hsa-miR-1285-3p, and lncRNA NPHP3-AS1 were likely to be associated with AF-VHD development.

CD4+ T cells and TGFß1/MAPK signal pathway involved in the valvular hyperblastosis and fibrosis in patients with rheumatic heart disease.

The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFß1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFß1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFß1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFß1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFß1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFß1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFß1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.

A Case of Aortic Valve Annulus Reconstruction with Bovine Pericardial Patch for Artificial Valve Detachment in Behcet's Disease.

A 36-year-old patient with Behcet's disease was hospitalized because of severe aortic valve regurgitation accompanied by aortic valve neoplasia and perforation of the valve body. In the first operation, we performed aortic valve replacement and ascending aortoplasty. The regular examination after surgery found no obvious regurgitation or discomfort. Four months later, however, the artificial valve fell off the valve frame and the annulus, with severe perivalvular leakage; the range of detachment was about two thirds. In the second operation, we applied a bovine pericardial patch. The aortic valve annulus was reconstructed using the lower edge of the bovine pericardial patch. The upper edge of the patch was sutured to the top of the aortic sinus to strengthen it, and the lateral edge was sutured 3 to 5 mm from the left coronary opening. The artificial valve was fixed well 6 months after the operation, and no valve detachment was observed. This method of reconstructing an aortic valve annulus with a bovine pericardial patch may be referential for preventing artificial valve detachment in patients with Behcet's disease.

The Perioperative Hyperchloremia Is Associated With Postoperative Acute Kidney Injury in Patients With off-Pump Coronary Artery Bypass Grafting: A Retrospective Study.

BACKGROUND: The relationship between perioperative hyperchloremia and postoperative acute kidney injury (AKI) is not well established. Our study aimed to evaluate the association between perioperative hyperchloremia and acute kidney injury in patients undergoing off-pump coronary artery bypass grafting (CABG). METHODS: Patients with coronary disease who underwent off-pump CABG between April 2017 and December 2019 were enrolled in this retrospective study. The patients with perioperative hyperchloremia were matched 1:1 to patients without perioperative hyperchloremia. The primary outcome was the postoperative acute kidney injury rate. The secondary outcomes included intensive care unit (ICU)-free days, postoperative hospitalization days, wound infection rate, and in-hospital mortality. Propensity score matching and univariate and multivariate logistic regression analyses were used in this study. RESULTS: A total of 321 patients who underwent off-pump CABG were included in the analysis. Propensity score matching selected 83 pairs for the final comparison. The results showed that the postoperative AKI rate was significantly different between the hyperchloremia and no hyperchloremia groups (56.6% versus 15.7%; P < .001). The number of ICU-free days, postoperative hospitalization days, wound infection rate, and in-hospital mortality were similar between the two groups. In the multivariable, logistic regression analysis, hyperchloremia was independently associated with the development of postoperative AKI (odds ratio [OR] = 1.814, 95% confidence interval [CI]: 1.072-3.070, P = .026). CONCLUSIONS: Perioperative hyperchloremia is associated with an increase in the postoperative AKI rate among patients undergoing off-pump CABG.

Molecular genetic characterization reveals linear tumor evolution in a pulmonary sarcomatoid carcinomas patient with a novel PHF20-NTRK1 fusion: a case report.

BACKGROUND: Pulmonary sarcomatoid carcinoma (SC) consists of both carcinomatous and sarcomatous tumors with high degree of malignancy, rapid progression, and poor prognosis. However, little is known regarding how pulmonary SC develops and progresses. CASE PRESENTATION: A 66-year-old male was initially diagnosed with stage IIIa lung cancer containing both adenocarcinoma (ADC) and SC. Adjuvant chemotherapy was administrated post-surgery, however, recurrence with SC only soon followed. Mutation profiling of the patient's microdissected ADC and SC components of the primary lesion and recurrent tumor was performed by targeted next-generation sequencing (NGS) of 416 cancer-relevant genes. Our data showed that primary SC/ADC and the recurrent SC shared multiple gene mutations including EGFR, NF1, TP53, CDKN2B, and SMARCA4, while both primary and recurrent SCs had a unique TP53 exon 4 splicing mutation frequently observed in sarcoma. Interestingly, a novel PHF20-NTRK1 fusion was acquired in the recurrent SC, which may be a potential driver for SC recurrence. CONCLUSIONS: The molecular genetic characteristics of tumor tissues at different stages reveals a linear tumor evolution model in this case, and support that the primary SC derived from the original lung ADC during the evolution of the tumor. We also identified a novel PHF20-NTRK1 fusion, which may contribute to the disease recurrence, and that can be potentially targeted with NTRK1 inhibitors for treatment.

Inhibiting polo-like kinase 1 enhances radiosensitization via modulating DNA repair proteins in non-small-cell lung cancer.

To assure faithful chromosome segregation, cells make use of the spindle assembly checkpoint, which can be activated in aneuploid cancer cells. In this study, the efficacies of inhibiting polo-like kinase 1 (PLK1) on the radiosensitization of non-small-cell lung cancer (NSCLC) cells were studied. Clonogenic survival assay was performed to identify the effects of the PLK1 inhibitor on radiosensitivity within NSCLC cells. Mitotic catastrophe assessment was used to measure the cell death and histone H2AX protein (γH2AX) foci were utilized to assess the DNA double-strand breaks (DSB). The transcriptome was analyzed via unbiased profiling of microarray expression. The results showed that the postradiation mitotic catastrophe induction and the DSB repair were induced by PLK1 inhibitor BI-6727, leading to an increase in the radiosensitivity of NSCLC cells. BI-6727 in combination with radiation significantly induced the delayed tumor growth. PLK1-silenced NSCLC cells showed an altered mRNA and protein expression related to DNA damaging, replication, and repairing, including the DNA-dependent protein kinase (DNAPK) and topoisomerase II alpha (TOPO2A). Furthermore, inhibition of PLK1 blocked 2 important DNA repair pathways. To summarize, our study showed PLK1 kinase as an option in the therapy of NSCLC.

Proteinase-Activated Receptor-2 Modulates Ve-Cadherin Expression to Affect Human Vascular Endothelial Barrier Function.

Published data indicate that the protease-activated receptor (PAR) 2 is involved in the pathogenesis of some cardiovascular diseases; the underlying mechanism is to be further investigated. Ve-cadherin is a critical molecule in maintaining the endothelial barrier integrity. This study aims to investigate the role of PAR2 activation in compromising the cardiac endothelial barrier function. In this study, human umbilical vein endothelial cells (Huvec cells) were cultured into monolayers using as an in vitro model of barrier function. The transepithelial electric resistance (TER) and permeability to dextran were assessed as indicators of barrier function. The expression of Ve-cadherin in Huvec cells was assessed by real-time RT-PCR, Western blotting, and chromatin immunoprecipitation. The results showed that exposure to tryptase in the culture, the barrier function of the Huvec monolayers, was markedly compromised; the levels of Ve-cadherin, one of the tight junction proteins, were suppressed as well. This was mimicked by exposing Huvec monolayers to the active PAR2 peptides (PAR2AP). After exposing to PAR2AP, the levels of histone deacetylase (HDAC)11 were increased in the Huvec cells. HDAC11 formed a complex with the transcription factor of Ve-cadherin to attenuate the Erg gene transcription activities and suppressed the expression of Ve-cadherin. In conclusion, activation of PAR2 compromises the vascular endothelial barrier function by suppressing the expression of Ve-cadherin. J. Cell. Biochem. 118: 4587-4593, 2017. © 2017 Wiley Periodicals, Inc.

miR-21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway.

BACKGROUND: Cardiac fibrosis play a key role in the atrial fibrillation pathogenesis but the underlying potential molecular mechanism is still understood. However, potential mechanisms for miR-21 upregulation and its role in cardiac fibrosis remain unclear. The controls cell proliferation and processes fundamental to disease progression. METHODS: In this study, immunohistochemistry, real-time RT-PCR, cell transfection, cell cycle, cell proliferation and Western blot were used, respectively. RESULTS: Here we have been demonstrated that the tumor suppressor cell adhesion molecule 1 (CADM1) is the potential target of miR-21. Our study revealed that miR-21 regulation of CADM1 expression, which was decreased in cardiac fibroblasts and fibrosis tissue. The cardiac fibroblasts transfected with miR-21 mimic promoted miR-21 overexpression enhanced STAT3 expression and decreased CADM1 expression. Nevertheless, the cardiac fibroblasts transfected with miR-21 inhibitor obtained the opposite expression result. Furthermore, downexpression of miR-21 suppressed cardiac fibroblast proliferation. CONCLUSIONS: These results suggested that miR-21 overexpression promotes cardiac fibrosis via STAT3 signaling pathway by decrease CADM1 expression, indicating miR-21 as an important signaling molecule for cardiac fibrotic remodeling and AF.

Epoxyeicosatrienoic acids act through TRPV4-TRPC1-KCa1.1 complex to induce smooth muscle membrane hyperpolarization and relaxation in human internal mammary arteries.

Human left internal mammary arteries (LIMAs) are commonly used as donor grafts for coronary bypass surgery. Previous reports suggested that 11,12-epoxyeicosatrienoic acid (11,12-EET) is an important endothelial-derived hyperpolarizing factor (EDHF) in human LIMAs and that EETs act through large conductance Ca²âº-activated K⁺ channels (KCa1.1) to induce smooth muscle cell hyperpolarization and relaxation in these tissues. In this study, we aimed to explore the role of vanilloid transient receptor potential channel 4 (TRPV4) and canonical transient receptor potential channel 1 (TRPC1) channels in the EET-induced smooth muscle hyperpolarization and vascular relaxation in human LIMAs. Co-immunoprecipitation studies demonstrated that TRPV4, TRPC1, and KCa1.1 physically interacted with each other to form a complex. Sharp microelectrode and vascular tension studies demonstrated that 11,12-EET (300 nmol/L) and 4α-phorbol 12,13-didecanoate (5 µmol/L) were able to induce smooth muscle membrane hyperpolarization and vascular relaxation in isolated human LIMA segments. The hyperpolarizing and relaxant effects were markedly reduced by treatments that could suppress the expression/activity of TRPV4, TRPC1, or KCa1.1. With the use of human embryonic kidney 293 cells that over-expressed with TRPV4, TRPC1 and KCa1.1, we found that TRPC1 is the linker through which TRPV4 and KCa1.1(α) can interact. The present study revealed that 11,12-EET targets the TRPV4-TRPC1-KCa1.1 complex to induce smooth muscle cell hyperpolarization and vascular relaxation in human LIMAs. This finding provides novel mechanistic insights for the EET action in human LIMAs.