Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α1 and ß-adrenergic receptors activation.

Sympathetic stress is prevalent in cardiovascular diseases. Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α1-ARs and ß-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1- and ß-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1-AR and ß-AR activation in the mice model by integrating transcriptome and proteome. We found that α1- and ß-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1-AR but not ß-AR led to neutrophil infiltration at one day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1-AR overactivation compared with ß-AR overactivation. These findings provide a new therapeutic strategy that, besides using ß-blocker as soon as possible, blocking α1-AR within one day should also be considered in the treatment of acute stress-associated cardiovascular diseases.

IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFß1 signaling pathway.

Upon chronic stress, ß-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by ß-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2-/- mice. Moreover, IMM-H007 inhibited transforming growth factor ß1 (TGFß1) expression in wild-type, but not AMPKα2-/- mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFß1 in both wild-type and AMPKα2-/- mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFß1, inhibits its binding to TGFß type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFß1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFß1 antagonist.

Glibenclamide alleviates ß adrenergic receptor activation-induced cardiac inflammation.

ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by ß-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the ß-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of ß-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates ß-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.

Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the ß-adrenergic receptor.

Acute sympathetic stress quickly induces cardiac inflammation and injury, suggesting that pathogenic signals rapidly spread among cardiac cells and that cell-to-cell communication may play an important role in the subsequent cardiac injury. However, the underlying mechanism of this response is unknown. Our previous study demonstrated that acute ß-adrenergic receptor (ß-AR) signaling activates inflammasomes in the heart, which triggers the inflammatory cascade. In the present study, ß-AR overactivation induced inflammasome activation in both the cardiomyocytes and cardiac fibroblasts (CFs) of mice hearts following a subcutaneous injection of isoproterenol (ISO, 5 mg/kg body weight), a selective agonist of ß-AR. In isolated cardiac cells, ISO treatment only activated the inflammasomes in the cardiomyocytes but not the CFs. These results demonstrated that inflammasome activation was propagated from cardiomyocytes to CFs in the mice hearts. Further investigation revealed that the inflammasomes were activated in the cocultured CFs that connected with cardiomyocytes via membrane nanotubes (MNTs), a novel membrane structure that mediates distant intercellular connections and communication. Disruption of the MNTs with the microfilament polymerization inhibitor cytochalasin D (Cyto D) attenuated the inflammasome activation in the cocultured CFs. In addition, the MNT-mediated inflammasome activation in the CFs was blocked by deficiency of the inflammasome component NOD-like receptor protein 3 (NLRP3) in the cardiomyocytes, but not NLRP3 deficiency in the CFs. Moreover, ISO induced pyroptosis in the CFs cocultured with cardiomyocytes, and this process was inhibited by disruption of the MNTs with Cyto D or by the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Z-YVAD-FMK (FMK). Our study revealed that MNTs facilitate the rapid propagation of inflammasome activation among cardiac cells to promote pyroptosis in the early phase of ß-adrenergic insult. Therefore, preventing inflammasome transfer is a potential therapeutic strategy to alleviate acute ß-AR overactivation-induced cardiac injury.

Grand Research Plan for Neural Circuits of Emotion and Memory--current status of neural circuit studies in China.

During recent years, major advances have been made in neuroscience, i.e., asynchronous release, three-dimensional structural data sets, saliency maps, magnesium in brain research, and new functional roles of long non-coding RNAs. Especially, the development of optogenetic technology provides access to important information about relevant neural circuits by allowing the activation of specific neurons in awake mammals and directly observing the resulting behavior. The Grand Research Plan for Neural Circuits of Emotion and Memory was launched by the National Natural Science Foundation of China. It takes emotion and memory as its main objects, making the best use of cutting-edge technologies from medical science, life science and information science. In this paper, we outline the current status of neural circuit studies in China and the technologies and methodologies being applied, as well as studies related to the impairments of emotion and memory. In this phase, we are making efforts to repair the current deficiencies by making adjustments, mainly involving four aspects of core scientific issues to investigate these circuits at multiple levels. Five research directions have been taken to solve important scientific problems while the Grand Research Plan is implemented. Future research into this area will be multimodal, incorporating a range of methods and sciences into each project. Addressing these issues will ensure a bright future, major discoveries, and a higher level of treatment for all affected by debilitating brain illnesses.

[National Natural Science Foundation of China promotes the development of Chinese medicine in China--an analysis of Chinese medicine project funded by National Natural Science Foundation of China in the last decade].

In recent years, projects funded by the Division V III of Health Sciences of the National Natural Science Foundation of China (NSFC) increased steadily, which enhanced the process of modernization of Chinese medicine (CM). We analyzed CM projects funded by NSFC during 2003 -2012, which aimed to provide reference to experts in the CM field.

An update on spinal cord injury research.

Spinal cord injury (SCI) can have a range of debilitating effects and permanently alter the capabilities and quality of life of survivors. The first specialized centers of care for SCI were established in 1944 and since then an increasing amount of research has been carried out in this area. Despite this, the present treatment and care levels for SCI are not comparable to those in other areas of medicine. In the clinic, the aim of SCI treatment is primarily to limit secondary damage by reducing compression in trauma spots and stabilizing the spinal column. Currently, no effective strategy for functional recovery is offered. In this review, we focus on research progress on the molecular mechanisms underlying SCI, and assess the treatment outcomes of SCI in animal models, i.e., neurotrophins and stem cells are discussed as pre-clinical therapies in animal models. We also assess the resources available and national research projects carried out on SCI in China in recent years, as well as making recommendations for the future allocation of funds in this area.

[Continuous funding of National Natural Science Foundation of China has boosted the development of the discipline of ophthalmology over the past 25 years].

OBJECTIVE: To analyze the role of National Natural Science Foundation of China (NSFC) on the development of the discipline of Ophthalmology from 1986 to 2010. METHODS: Data on the total number of projects and funding of NSFC allocated to Ophthalmology, as well as papers published, awards, personnel training, subject construction were collected, and the role of NSFC on other sources of funding was evaluated. RESULTS: From 1986 to 2010, NSFC supported a total of 593 scientific research projects of Ophthalmology, funding a total amount of 152.44 million Yuan, among which were 371 free application projects, 156 Young Scientist Funds, 9 Key Programs, 5 National Science Fund for Distinguished Young Scholars, 3 Major international (regional) joint research programs, 1 Science Fund for Creative Research Group and 48 other projects. Over the past 25 years, the number of NSFC projects received by Ophthalmology has been an overall upward trend in the share in the Department of Life (Health) Sciences. Take the projects (186 of 292, 63.7%) as examples completed between 2002 and 2010, a total 262 papers were published in Science Citation Index (SCI) included journals and 442 papers were published in Chinese journals. Meanwhile, 8 Second prizes of National Science and Technology Progress Award and 1 State Technological Invention Award were received. As of 2010, the training of a total of more than 40 postdoctoral, more than 400 doctoral students and more than 600 graduate students have been completed. 5 national key disciplines and 1 national key laboratory have been built. Moreover, 2 "973" programs from Ministry of Science and Technology and 1 project of special fund in the public interest from Ministry of Public Health were obtained. 2 scholars were among the list of Yangtze Fund Scholars granted by Ministry of Education. CONCLUSIONS: Over the past 25 years, a full range of continuous funding from NSFC has led to fruitful results and a strong impetus to the progress of discipline of Ophthalmology.

[The support of National Natural Science Foundation of China prompts the progress and development of basic research of dental and craniofacial research: a 25 years review].

OBJECTIVE: To investigate the effect of National Natural Science Foundation of China (NSFC) on the progress of dental research from 1986 to 2010. METHODS: The data regarding the NSFC allocated to dental and craniofacial research from 1986 to 2010 were collected. Total expenses and numbers of the majority of programs and the situation of completed program finished in recent 7 years were provided. RESULTS: From 1986 to 2010, a total of 922 projects and 204 401 thousands Chinese Yuan supported by NSFC were allocated to dental research. The detailed allocations were as follows: general program (564), young scientists fund (258), regional fund (40), key program (11), national science fund for distinguished young scholars (5), major international (regional) joint research program (1), others (43). The grants of talent training increased dramatically. Taking the projects (307) completed between 2003 and 2009 for example, 307 papers were published in Science Citation Index (SCI) included journals and 1049 papers were published on Chinese journals. By the time of completion of the projects, 39 post-doctoral students, 590 students for PhD degree and 670 students for Master degree had been trained. CONCLUSIONS: Over the past 25 years, the continuous increase of NSF on dental research has led to substantial achievement, resulting in great progress of dental oral-cranio-facial research.

Ca2+ participates in alpha1B-adrenoceptor-mediated cAMP response in HEK293 cells.

AIM: To investigate the alpha1B-adrenoceptor (alpha1B-AR)-mediated cAMP response and underlying mechanisms in HEK293 cells. METHODS: Full-length cDNA encoding alpha1B-AR was transfected into HEK293 cells using the calcium phosphate precipitation method, and alpha1B-AR expression and cAMP accumulation were determined by using the saturation radioligand binding assay and ion-exchange chromatography, respectively. RESULTS: Under agonist stimulation, alpha1B-AR mediated cAMP synthesis in HEK293 cells, and blockade by PLC-PKC or tyrosine kinase did not reduce cAMP accumulation induced by NE. Pretreatment with pertussis toxin (PTX) had little effect on basal cAMP accumulation as well as norepinephrine (NE)-stimulated cAMP accumulation. In addition, pretreatment with cholera toxin (CTX) neither mimicked nor blocked the effect induced by NE. The extracellular Ca2+ chelator egtazic acid (EGTA), nonselective Ca2+ channel blocker CdCl2 and calmodulin (CaM) inhibitor W-7 significantly reduced NE-induced cAMP accumulation from 1.59%+/-0.47% to 1.00%+/-0.31%, 0.78%+/-0.23%, and 0.90%+/-0.40%, respectively. CONCLUSION: By coupling with a PTX-insensitive G protein, alpha1BAR promotes Ca2+ influx via receptor-dependent Ca2+ channels, then Ca2+ is linked to CaM to form a Ca2+-CaM complex, which stimulates adenylyl cyclase (AC), thereby increasing the cAMP production in HEK293 cell lines.

Morphological and electrophysiological study on the inferior nodal extension and transitional cellular band in the rabbit atrioventricular junctional area.

BACKGROUND: Advances in catheter ablation procedures for the treatment of supraventricular arrhythmias have created the need to understand better the morphological and electrophysiological characteristics of the inferior nodal extension (INE) and transitional cellular band (TCB) in the atrioventricular (AV) junctional area. METHODS: Firstly, we observed the histological features of 10 rabbit AV junctional areas by serial sections under light microscopy. Then we recorded the action potentials (APs) of transitional cells (TCs) in the INE, TCBs, AV node, and ordinary right atrial myocytes from the AV junctional area of 30 rabbits using standard intracellular microeletrode techniques. RESULTS: Under light microscopy, the INE appeared to be mostly composed of transitional cells linking upward to the AV node. Four smaller TCBs originated in the orifice of the coronary sinus, the region between the septal leaflet of the tricuspid valve and the coronary sinus, the inferior wall of the left atrium, and the superior interatrial septum, respectively, all linking to the INE or the AV node. Compared with ordinary atrial myocytes, the AP of the TCs in both the INE and the TCBs had a spontaneous phase 4 depolarization (not present in ordinary atrial myocytes), with a less negative maximum diastolic potential, a smaller amplitude, a slower maximum velocity of AP upstroke, and a longer action potential duration at 50% repolarization (APD50) and at 30% repolarization (APD30). The AP characteristics of these TCs were similar to those of the AV node, except that the velocities of the phase 4 spontaneous depolarization were slower and their action potential durations at 90% repolarization (APD90) were shorter. Moreover, APD50 and APD30 of the TCs of the TCBs were shorter than in the case of TCs of the AV node. CONCLUSIONS: The TCs of the INE and TCBs are similar to slow response automatic cells. They provide a substrate for slow pathway conduction. In addition, repolarization heterogeneity exists in the AV junctional area.

Characterization of cAMP accumulation mediated by three alpha1-adrenoceptor subtypes in HEK293 cells.

AIM: To investigate the characterization of cAMP response mediated by alpha1-adrenoceptor (alpha1-AR) subtypes in HEK293 cells. METHODS: (1) Full-length cDNA encoding three alpha1-AR subtypes were transfected into HEK293 cells by the calcium phosphate precipitation method, respectively. (2) The densities of alpha1-AR subtypes expressed in HEK293 cells were measured by radioligand binding assay. (3) cAMP accumulation was measured by [3H]adenine prelabeling method. RESULTS: (1) Activation of each of three subtypes resulted in an increase of cAMP accumulation in HEK293 cells in a dose-dependent manner, which was inhibited by selective alpha1-AR antagonist prazosin. (2) Comparing the pharmacological property, the maximal responses of alpha1A-AR to agonists were the most potent, while the sensitivity of alpha1-AR subtypes to norepinephrine (NE) was the highest. CONCLUSION: Each of three alpha1-AR subtypes can mediate cAMP accumulation in HEK293 cell line, and there are differences in pharmacological property.