Marsdenia tenacissima genome reveals calcium adaptation and tenacissoside biosynthesis.

Marsdenia tenacissima is a medicinal plant widely distributed in the calcium-rich karst regions of southwest China. However, the lack of a reference genome has hampered the implementation of molecular techniques in its breeding, pharmacology and domestication. We generated the chromosome-level genome assembly in Apocynaceae using combined SMRT sequencing and Hi-C. The genome length was 381.76 Mb, with 98.9% of it found on 11 chromosomes. The genome contained 222.63 Mb of repetitive sequences and 21 899 predicted gene models, with a contig N50 of 6.57 Mb. Phylogenetic analysis revealed that M. tenacissima diverged from Calotropis gigantea at least 13.43 million years ago. Comparative genomics showed that M. tenacissima underwent ancient shared whole-genome duplication. This event, together with tandem duplication, contributed to 70.71% of gene-family expansion. Both pseudogene analysis and selective pressure calculations suggested calcium-related adaptive evolution in the M. tenacissima genome. Calcium-induced differentially expressed genes (DEGs) were mainly enriched in cell-wall-related processes. Domains (e.g. Fasciclin and Amb_all) and cis-elements (e.g. MYB and MYC) frequently occurred in the coding and promoter regions of cell-wall DEGs, respectively, and the expression levels of these genes correlated significantly with those of calcium-signal-related transcription factors. Moreover, calcium addition increased tenacissoside I, G and H contents. The availability of this high-quality genome provides valuable genomic information for genetic breeding and molecular design, and lends insights into the calcium adaptation of M. tenacissima in karst areas.

Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension.

BACKGROUND: The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. RESULTS: Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P = 0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group. CONCLUSIONS: In older patients with hypertension, intensive treatment with a systolic blood-pressure target of 110 to less than 130 mm Hg resulted in a lower incidence of cardiovascular events than standard treatment with a target of 130 to less than 150 mm Hg. (Funded by the Chinese Academy of Medical Sciences and others; STEP ClinicalTrials.gov number, NCT03015311.).

Changes in microRNA Expression Profiles in Diabetic Cardiomyopathy Rats Following H3 Relaxin Treatment.

ABSTRACT: MicroRNAs (miRNAs) are noncoding RNAs that play an important role in the mechanisms of diabetic cardiomyopathy (DCM); however, whether human recombinant relaxin-3 (H3 relaxin) inhibits myocardial injury in DCM rats and the underlying mechanisms involving miRNAs remain unknown. miRNA expression profiles were detected using miRNA microarray and bioinformatics analyses of myocardial tissues from control, DCM, and H3 relaxin-administered DCM groups, and the regulatory mechanisms of the miRNAs were investigated. A total of 5 miRNAs were downregulated in the myocardial tissues of DCM rats and upregulated in H3 relaxin-treated DCM rats, and 1 miRNA (miRNA let-7d-3p) was increased in the myocardial tissue of DCM rats and decreased in H3 relaxin-treated DCM rats as revealed by miRNA microarray and validated by real-time polymerase chain reaction. Important signaling pathways were found to be triggered by the differentially expressed miRNAs, including metabolism, cancer, Rap1, PI3K-Akt, and MAPK signaling pathways. The study revealed that H3 relaxin improved glucose uptake in DCM rats, potentially via the regulation of miRNA let-7d-3p.

Identifying mineral decrement with bone injury by quantifying osteocalcin on current-volt sensor.

Osteoporosis, a bone disease is caused by the deterioration of bone and shows an enhanced risk of bone fracture and decreasing bone mineral density. Unfortunately, the available radiological techniques are expensive, and have disadvantages such as radiation intake, need a specialist to handle the instrument, and so forth. This research is focused to develop a point-of-care system to identify osteocalcin on current-volt sensor, which helps to diagnose the bone metabolism and prognostics. Antiosteocalcin antibody was attached on the electrode through the silane-modified iron material. The antibody-immobilized sensing surface was utilized to identify the level of osteocalcin and the detection limit of 100 pg/ml reached on linear concentrations of 0.01-3000 ng/ml. Calculations were made by triplicates (n = 3; 3δ) on the determination coefficient of y = 0.2637x-0.6012; R2 = 0.9319. Further, control proteins failed to bind with immobilized antibody, confirmed by the specific osteocalcin detection. This research is to identify the osteoporosis biomarker and to help determine the conditions with osteoporosis.

Inflammatory cytokines enhance procoagulant activity of platelets and endothelial cells through phosphatidylserine exposure in patients with essential hypertension.

The exact mechanism of the prothrombotic state of essential hypertension (EH) patients remains elusive. Our objective was to assess whether phosphatidylserine (PS) exposure on endothelial cells (ECs), platelets, and microparticles (MPs) can account for the hypercoagulability in EH patients. PS exposure on cells and MPs, mainly from platelets and ECs was analyzed with flow cytometry. Procoagulant activity (PCA) was evaluated by purified coagulation complex assays, clotting time, and fibrin turbidity. We found that EH patients exhibited elevated levels of PS+ platelets, serum-cultured ECs, MPs, endothelial-derived MPs and platelet-derived MPs compared to the controls (all P < 0.05). Moreover, platelets and MPs from the patients and their sera-cultured ECs showed markedly enhanced intrinsic/extrinsic FXa, thrombin, and fibrin generation, and greatly shortened coagulation time. This PCA could be blocked approximately 80%, by the addition of lactadherin. Furthermore, we detected elevated levels of IL-8, IL-6, and TNF-α in EH patients could activate platelets/ECs and induce elevated PS exposure on their membranes. Our results suggest that inflammatory cytokines could enhance procoagulant activity of platelets and endothelial cells via their PS exposure in EH patients. As such, a PS blockade may be a viable therapeutic strategy for treating such patients.

May Measurement Month 2019: an analysis of blood pressure screening results from China.

To report the blood pressure (BP) data obtained in the May Measurement Month (MMM) 2019 in China. Study participants were recruited if ≥18 years of age and had ideally not had their BP measured for ≥1 year. BP was measured three times consecutively with a 1-min interval in the sitting position, using a validated electronic BP monitor. Trained volunteer investigators administered a questionnaire to collect information on lifestyle, medical history, and use of medications. The measurement was performed in 238 387 participants in 250 sites across 31 China provinces. The majority of screening took place in hospitals or clinics (78.7%), with 17.1% in outdoor public areas and 4.2% in other settings. The study participants included 127 853 women (53.6%) and had a mean (±SD) age of 48.9 ± 16.2 years. The mean (of readings two and three) systolic/diastolic BP was 121.8/73.8 mmHg. In all hypertensive patients (n = 66 181, 27.8%), the awareness, treatment, and control rates of hypertension were 51.5%, 48.4%, and 29.1%, respectively. Linear regression models showed differences in systolic and diastolic BP according to sex and age and several other major characteristics, such as previous stroke, myocardial infarction, and diabetes mellitus, antihypertensive medication use and known hypertension, previous hypertension in pregnancy and current pregnancy, alcohol intake and current smoking, and body mass index. The MMM 2019 campaign has been successful in measuring BP in a large member of participants in China.

Calhex231 ameliorates myocardial fibrosis post myocardial infarction in rats through the autophagy-NLRP3 inflammasome pathway in macrophages.

The calcium-sensing receptor (CaSR) is involved in the pathophysiology of many cardiovascular diseases, including myocardial infarction (MI) and hypertension. The role of Calhex231, a specific inhibitor of CaSR, in myocardial fibrosis following MI is still unclear. Using Wistar rats, we investigated whether Calhex231 ameliorates myocardial fibrosis through the autophagy-NLRP3 inflammasome pathway in macrophages post myocardial infarction (MI). The rats were randomly divided into sham, MI and MI + Calhex231 groups. Compared with the sham rats, the MI rats consistently developed severe cardiac function, myocardial fibrosis and infiltration of inflammatory cells including macrophages. Moreover, inflammatory pathway including activation of NLRP3 inflammasome, IL-1ß and autophagy was significantly up-regulated in myocardial tissue, infiltrated cardiac macrophages and peritoneal macrophages of the MI rats. These impacts were reversed by Calhex231. In vitro, studies revealed that calindol and rapamycin exacerbated MI-induced autophagy and NLRP3 inflammasome activation in peritoneal macrophages. Calhex231 and 3-Methyladenine (a specific inhibitor of autophagy) attenuated both autophagy and NLRP3 inflammasome activation; however, the caspase-1 inhibitor Z-YVAD-FMK did not. Our study indicated that Calhex231 improved cardiac function and ameliorated myocardial fibrosis post MI, likely via the inhibition of autophagy-mediated NLRP3 inflammasome activation; this provides a new therapeutic target for ventricular remodelling-related cardiovascular diseases.

Blockade of IL-6 alleviates bone loss induced by modeled microgravity in mice.

This study investigated the effects of blockade of IL-6 on bone loss induced by modeled microgravity (MG). Adult male mice were exposed to hind-limb suspension (HLS) and treated with IL-6-neutralizing antibody (IL-6 nAb) for 4 weeks. HLS in mice led to upregulation of IL-6 expression in both sera and femurs. IL-6 nAb treatment in HLS mice significantly alleviated bone loss, evidenced by increased bone mineral density of whole tibia, trabecular thickness and number, bone volume fraction of proximal tibiae, and ultimate load and stiffness of femoral diaphysis. IL-6 nAb treatment in HLS mice significantly enhanced levels of osteocalcin in sera and reduced levels of deoxypyridinoline. In MC3T3-E1 cells exposed to MG in vitro, IL-6 nAb treatment increased mRNA expression and activity of alkaline phosphatase, mRNA expression of osteopontin and runt-related transcription factor 2, and protein levels of osteoprotegerin and decreased protein levels of receptor activator of the NF-κB ligand. In RAW254.7 cells exposed to MG, IL-6 nAb treatment downregulated mRNA expression of cathepsin K and tartrate-resistant acid phosphatase (TRAP) and reduced numbers of TRAP-positive multinucleated osteoclasts. In conclusion, blockade of IL-6 alleviated the bone loss induced by MG.

FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC ß2 pathway.

Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)-induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)-induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC ß2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte-specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC ß2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.

H2 relaxin ameliorates angiotensin II-induced endothelial dysfunction through inhibition of excessive mitochondrial fission.

The physiological function of endothelial cells plays an important role in maintaining normal cardiovascular function. Endothelial dysfunction induced by AngII (angiotensin II) is the pathological mechanism of occurrence and development of cardiovascular diseases. Human recombinant relaxin-2 (H2 relaxin), which has protective effect on cardiovascular functions, ameliorates damage to endothelial cells induced by angiotensin II (AngII) treatment. However, the exact mechanisms remain unclear. In this study, we researched the mechanisms of H2 relaxin inhibiting AngII-induced endothelial dysfunction from the protective effect of H2 relaxin on endothelial function though inhibiting excessive mitochondrial fission. Here, we found that H2 relaxin increased eNOS, SOD1 expression, inhibited excessive mitochondrial fission and decreased ROS level in HUVECs treated with AngII. However, overexpression of fission protein 1 (Fis1) prevented H2 relaxin from protecting against AngII-induced low eNOS, SOD1 expression, excessive mitochondrial fission and increased ROS level in HUVECs. Our study indicated that excessive mitochondrial fission could be a target for H2 relaxin to treat endothelial dysfunction in angiocardiopathy.

Quercetin prevents necroptosis of oligodendrocytes by inhibiting macrophages/microglia polarization to M1 phenotype after spinal cord injury in rats.

BACKGROUND: Oligodendrocytes (OLs) death after spinal cord injury (SCI) contributes to demyelination, even leading to a permanent neurological deficit. Besides apoptosis, our previous study demonstrated that OLs underwent receptor-interacting serine-threonine kinase 3(RIP3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. Considering that necroptosis is always accompanied with pro-inflammatory response and quercetin has long been used as anti-inflammatory agent, in the present study we investigated whether quercetin could inhibit necroptosis of OLs and suppress the M1 macrophages/microglia-mediated immune response after SCI as well as the possible mechanism. METHODS: In this study, we applied quercetin, an important flavonoid component of various herbs, to treat rats with SCI and rats injected with saline were employed as the control group. Locomotor functional recovery was evaluated using Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay. In vivo, the necroptosis, apoptosis, and regeneration of OLs were detected by immunohistochemistry, 5'-bromo-2'-deoxyuridine (BrdU) incorporation. The loss of myelin and axons after SCI were evaluated by Luxol fast blue (LFB) staining, immunohistochemistry, and electron microscopic study. The polarization of macrophages/microglia after SCI and the underlying mechanisms were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. In vitro, the ATP and reactive oxygen species (ROS) level examination, propidium iodide (PI) labeling, and Western blotting were used to analyze the necroptosis of cultured OLs, while the signaling pathways-mediated polarization of cultured macrophages/microglia was detected by qRT-PCR and Western blotting. RESULTS: We demonstrated that quercetin treatment improved functional recovery in rats after SCI. We then found that quercetin significantly reduced necroptosis of OLs after SCI without influencing apoptosis and regeneration of OLs. Meanwhile, myelin loss and axon loss were also significantly reduced in quercetin-treated rats, as compared to SCI + saline control. Further, we revealed that quercetin could suppress macrophages/microglia polarized to M1 phenotype through inhibition of STAT1 and NF-κB pathway in vivo and in vitro, which contributes to the decreased necroptosis of OLs. CONCLUSIONS: Quercetin treatment alleviated necroptosis of OLs partially by inhibiting M1 macrophages/microglia polarization after SCI. Our findings suggest that necroptosis of OLs may be a potential therapeutic target for clinical SCI.

Treatment with hydrogen sulfide donor attenuates bone loss induced by modeled microgravity.

The present study was undertaken to explore the therapeutic potential of hydrogen sulfide against bone loss induced by modeled microgravity. Hindlimb suspension (HLS) and rotary wall vessel bioreactor were applied to model microgravity in vivo and in vitro, respectively. Treatment of rats with GYY4137 (a water soluble donor of hydrogen sulfide, 25 mg/kg per day, i.p.) attenuated HLS-induced reduction of bone mineral density in tibiae, and preserved bone structure in tibiae and mechanical strength in femurs. In HLS group, GYY4137 treatment significantly increased levels of osteocalcin in sera. Interestingly, treatment of HLS rats with GYY4137 enhanced osteoblast surface, but had no significant effect on osteoclast surface of proximal tibiae. In MC3T3-E1 cells exposed to modeled microgravity, GYY4137 stimulated transcriptional levels of runt-related transcription factor 2 and enhanced osteoblastic differentiation, as evidenced by increased mRNA expression and activity of alkaline phosphatase. HLS in rats led to enhanced levels of interleukin 6 in sera, skeletal muscle, and tibiae, which could be attenuated by GYY4137 treatment. Our study showed that GYY4137 preserved bone structure in rats exposed to HLS and promoted osteoblastic differentiation in MC3T3-E1 cells under modeled microgravity.

The association of metabolic syndrome components and chronic kidney disease in patients with hypertension.

BACKGROUND: Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension. METHODS: We carried out a multi-center cross-sectional study from Apr. 2017- Apr. 2018 in 15 cities in China. RESULTS: A total of 2484 patients with hypertension were enrolled. Among them, 56% were male and the average age was 65.12 ± 12.71 years. The systolic BP/diastolic BP was 142 ± 18/83 ± 12 mmHg. Metabolic syndrome components turned out to be highly prevalent in patients with hypertension, ranging from 40 to 58%. The prevalence of chronic kidney disease reached 22.0%. Multi-variate logistic analysis revealed that elevated triglyceride (TG) (OR = 1.81, 95% CI 1.28-2.57, p < 0.01), elevated fasting blood glucose (FBG) (OR = 1.43, 95% CI 1.00-2.07, p = 0.05) and hypertension grades (OR = 1.20, 95% CI 1.00-1.44, p = 0.05) were associated with the prevalence of CKD. In sub-group analysis, elevated TG remained strongly associated with CKD in both diabetes (OR = 2.10, 95%CI 1.22-3.61, p < 0.01) and non-diabetes (OR = 1.53, 95% CI 1.09-2.16, p = 0.01). In sub-group analysis of hypertension grades, there was also a graded trend between elevated TG and CKD from controlled blood pressure (BP) to hypertension grade 2 (OR = 1.81, 95%CI 1.06-3.11, p = 0.03; OR = 1.85, 95%CI 1.00-3.43, p = 0.05; OR = 2.81, 95% CI 1.09-7.28, p = 0.03, respectively). CONCLUSION: Elevated TG, elevated FBG and hypertension grades were significantly associated with the prevalence of CKD in patients with hypertension. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades.

NLRP3 Inflammasome Is Involved in Calcium-Sensing Receptor-Induced Aortic Remodeling in SHRs.

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.

Comparison of clinical results between novel percutaneous pedicle screw and traditional open pedicle screw fixation for thoracolumbar fractures without neurological deficit.

OBJECTIVES: To compare the efficacy and safety of novel percutaneous minimally invasive pedicle screw fixation and traditional open surgery for thoracolumbar fractures without neurological deficit. METHODS: Sixty adult patients with single thoracolumbar fracture between June 2014 and June 2016 were recruited in this study, randomly divided into open fixation group (group A) or minimally invasive percutaneous fixation group (group B). Clinical and surgical evaluation including surgery time, blood losses, radiation times, hospital stay, and complication were performed. The two groups of patients with pre-operative and last follow-up anterior height ratio of fracture vertebral, Cobb angle of fracture vertebral, and VAS score of back pain were compared. RESULTS: All patients completed valid follow-ups, with an average time period of 15.4 months (12-26 months). Group B achieved much better results in time of operation, intra-operative blood loss, and length of stay than group A (P < 0.05). Group A was significantly better than group B in the times of radiation (P < 0.05). The VAS score was significantly lower in group B than in group A at three days after the operation (P < 0.05). There were no significant differences between the two groups in the anterior height ratio of fracture vertebral, Cobb angle, and VAS score in the last follow-up (P > 0.05). No injured nerve or other severe complications occurred in both groups; one of the patients from group A had back and loin pain lasting for about one month, which resolved after analgesia and functional training. There was no significant difference between the two groups in incidence of complications. CONCLUSIONS: Novel percutaneous pedicle screws with angle reset function can achieve the same effect as traditional open pedicle screw fixation in the treatment of thoracolumbar fractures without nerve injuries. Percutaneous minimally invasive pedicle screw fixation has the characteristics of shorter operative time, less bleeding, and less pain, but it needs more radiation times.

H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose.

Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase-1 activation, interleukin-1ß (IL-1ß) and IL-18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high-glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS- and P2X7R-mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome-mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome-mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.

Activation of calcium-sensing receptor-mediated autophagy in angiotensinII-induced cardiac fibrosis in vitro.

Cardiac fibrosis is one of the primary mechanisms of ventricular remodeling, and there is no effective method for reversal. Activation of calcium sensing receptor (CaSR) has been reported to be involved in the development of myocardial fibrosis, but the molecular mechanism for CaSR activation has not yet been clarified and needs to be further explored. Here, we found that AngII induces cardiac fibroblast proliferation and phenotypic transformation in a dose-dependent manner with increased CaSR and autophagy related protein (Beclin1, LC3B) expression. CaSR activation results in intracellular calcium release, MEK1/2 pathway phosphorylation, autophagy activation and collagen formation induced by AngII in cardiac fibroblasts. However, pretreating the cells with Calhex231, PD98059 or 3-MA partially blocked AngII-induced cardiac fibrosis. Our data indicate that the activation of CaSR-mediated MEK/ERK and autophagic pathways is involved in AngII-induced cardiac fibrosis in vitro.

Nox4-dependent ROS production is involved in CVB3-induced myocardial apoptosis.

Viral myocarditis is a cardiovascular disease that seriously affects human health. Its mechanism is not clear. Coxsackievirus B3 (CVB3) is a member of the picornavirus family and is the leading cause of viral myocarditis. Our group tested the genes in a mouse model of CVB3 virus infection and confirmed that the NADPH oxidase gene had a high expression trend in the acute phase of infection. Whether Nox4, the homologue of NADPH oxidase, participates in the process of viral myocarditis has not been reported. In this study, we found increased expression of Nox4 in viral myocarditis in vivo and in vitro. DPI is a non-specific inhibitor of Nox4 that improved CVB3-induced myocarditis after injection in vivo. DPI also inhibited intracellular ROS release and apoptosis in vitro. Our data indicated that Nox4-dependent ROS production was involved in CVB3-induced myocardial apoptosis.

Involvement of mitochondrial fission in calcium sensing receptor-mediated vascular smooth muscle cells proliferation during hypertension.

Hyperproliferation of vascular smooth muscle cells (VSMC) is a major risk factor for cardiovascular diseases. Proper mitochondrial fission and fusion is involved with VSMC function. However, the role and mechanism of mitochondrial morphological changes in VSMC proliferation are not well understood. Here, we found that calcium sensing receptor (CaSR) was increased in the aortas from spontaneous hypertensive rats (SHRs) compared with age-matched Wistar Kyoto (WKY) rats. There was also an increase in mitochondrial fission and VSMC proliferation, which was attenuated by Calhex231. In primary rat VMSC, angiotensin II (Ang II) stimulation induced cytosolic [Ca2+]i increase, mitochondrial shortening and proliferation, all of which could be attenuated by pretreatment with mitochondrial division inhibitor-1 (Mdivi-1) and Calhex231. Our data indicate that CaSR-mediated mitochondrial fission could be a therapeutic target for hyperproliferative disorders.

BACE1 regulates the proliferation and cellular functions of Schwann cells.

BACE1 is an indispensable enzyme for generating ß-amyloid peptides, which are excessively accumulated in brains of Alzheimer's patients. However, BACE1 is also required for proper myelination of peripheral nerves, as BACE1-null mice display hypomyelination. To determine the precise effects of BACE1 on myelination, here we have uncovered a role of BACE1 in the control of Schwann cell proliferation during development. We demonstrate that BACE1 regulates the cleavage of Jagged-1 and Delta-1, two membrane-bound ligands of Notch. BACE1 deficiency induces elevated Jag-Notch signaling activity, which in turn facilitates proliferation of Schwann cells. This increase in proliferation leads to shortened internodes and decreased Schmidt-Lanterman incisures. Functionally, evoked compound action potentials in BACE1-null nerves were significantly smaller and slower, with a clear decrease in excitability. BACE1-null nerves failed to effectively use lactate as an alternative energy source under conditions of increased physiological activity. Correlatively, BACE1-null mice showed reduced performance on rotarod tests. Collectively, our data suggest that BACE1 deficiency enhances proliferation of Schwann cell due to the elevated Jag1/Delta1-Notch signaling, but fails to myelinate axons efficiently due to impaired the neuregulin1-ErbB signaling, which has been documented.