NRG ErbB role in angiogenesis

1998 Russell et al in matrix culture without growth factor in human umbilical vein endothelial cells (HUVEC), the addition of recombinant NRG 3 (a ErbB3 ErbB4 ligand) culture 10d, found that NRG 3 (100ng ml) allows the number of HU VEC an increase of 25 times with 10ng ml the effect of vascular endothelial growth factor (VEGF). Applications can significantly inhibit VEGF-stimulated cells increase in the number of anti-VEGF antibody, but not affect NRG 3 due to the number of HUVEC increased, indicating that NRG 3 HUVEC proliferation effect has nothing to do with VEGF. HUVEC, its application of the two-dimensional collagen gel matrix culture by adding 24 ~ 36h after NRG 3 lumen-like structures formed lengthwise in HUVEC, will not affect the anti-VEGF antibody NRG this angiogenic effect. Corneal angiogenesis model in rats applications containing different doses of NRG or VEGF sustained-release tablets implanted eyes of 7d found, 10ngNRG can induce new blood vessel formation, 50ng can significantly promote new blood vessel formation; role of VEGF similar but does not rely on VEGF. Bagheri is found that The HRG stimulate of breast cancer the epithelial cells VEGFmRNA and protein expression, adding HRG1 to 9hVEGFmRNA increased 2-6 times, can stimulate endothelial cells to produce luminal-like structure, the application of anti-HER2 monoclonal antibody or anti-VEGF monoclonal antibodies this effect can be blocked, this angiogenesis is VEGF dependent. Yen also observed in other tumor cells to a similar result.

Neuromodulation and Its ErbBs receptors in the cardiovascular system

Neuregulin (Neuregulins, NRGs), a member of the epidermal growth factor (EGF) family, a local role of polypeptide regulatory factors, plays an important role of the nervous system, such as NRGs promote the proliferation of Schwann cells and glial cells, differentiation adhesion, migration, and survival. Known NRGs, NRG1, NRG2, NRG3 and NRG4 four subtypes. The NRG1 Department with a gene encoding a product separation and purification and cloning in different laboratories, it is a different name, such as neu differentiation factor (of neu differentiationfactor NDF), human heregulin (HRG), glial growth factor (GGF) and acetylcholine the re ceptor inducing the activity (ARIA). In addition, three different genes encoding other types of neuregulin, respectively, NRG2, NRG3 and NRG4. Functional receptors for NRGs ErbBs, also known as epidermal growth factor receptor (EGFR), including four subtypes: ErbB1 of EGFR, ErbB2 of HER2 of neu of ErbB3 of HER3 and ErbB4 is HER4. NRGs and ErbBs receptor activation of the ErbB receptor tyrosine kinase induced by a wide range of biological effects, such as cell proliferation, differentiation, migration, adhesion, survival. Recent studies have shown that NRG of ErbB signaling pathway also plays an important role in the development process of the cardiovascular system, and to participate in the pathogenesis of cardiac hypertrophy.

The NRG ErbB the cardiovascular effects

The role of experiments in heart development, the NRGs, ErbB2 and ErbB4 an important role in the development of the nervous system and the heart. NRG ErbB promote the proliferation of cardiomyocytes, hypertrophic growth inhibition of cardiomyocyte apoptosis and promote cell survival. GGF2 to promote embryonic rat neonatal rat cardiac myocytes DNA synthesis, and promote an increase in the number of myocardial cells. A net increase of the number of functional myocardial cells in the embryonic heart development process, related with the proliferation of myocardial cells, is still associated with myocardial cell survival. Study also observed that nearly 25% of the cells in serum-free matrix in primary cultures of neonatal rat cardiac myocytes number 4d died; contrary, a 30% increase in the number of cells added GGF2 GGF2 promote survival of cardiomyocytes in vitro . Expression the no function NRGs and ErbBs rats died of heart and nervous system abnormalities in the uterus. NRG1, ErbB2, ErbB3, ErbB4 is no function of the mutated gene experiments showed that embryonic mice, mutations in several other genes outside than ErbB3 and development 10. 5d, due to poor cardiac differentiation, lack of ventricular trabeculae and endocardial cushion while resulting in the death of the embryo. Hertig application NRG1 and insulin-like growth factor diffuses into the chambers of the heart found, NRG1 can promote the formation of trabecular ventricular wall, and insulin-like growth factor 1 had no effect. In addition, NRG1 and insulin-like growth factor 1 synergistically induced cardiomyocyte DNA synthesis, and promote the growth of the ventricular tight zone and AV cushion after two heart chamber development and maturation of the key. Prompt the NRG1 and insulin-like growth factor 1 interaction occurs affect the morphology of the heart chamber. Zhao et GGF2 with other pro-mitogen not identical, in serum-free low density alkylene fusion myocardial cell culture, GGF2 mechanism to promote the survival of neonatal and adult cardiomyocytes, in part is due to inhibition of apoptosis.

The cardiovascular system NRG ErbB widely expressed in the cardiovascular system

The cardiovascular system NRG ErbB widely expressed in the cardiovascular system, but differences in their distribution in different tissues. Mainly distributed in the intima of developing ventricular NRG1mRNA, NRG2 mRNA is mainly distributed in the intima of developing atrial NDF (neu 1mR NA) expression in rat coronary microvascular endothelial cells in cardiac development and pathological hypertension are induced cardiac hypertrophy, myocardial cells and neighboring endothelial cells highly expressed NRGs. While rat embryonic development of the mid-ErbB2, ErbB3 and ErbB4 expression After ErbB3 expression was significantly down-regulated. ErbB2, ErbB4 distribution in atrial and ventricular myocardium, ErbB3 distributed in the mesenchymal cells in the endocardial cushion and Cordis ball. In human umbilical vein endothelial cells detected immune response kind of ErbB2, ErbB3 and ErbB4

Nervous system and other tissues in the nervous system of the neurons, astrocytes, oligodendrocytes, glial cells and Schwann cells receptor expression are ErbBs. Retinal neurons, breast cancer cells have NRGs distribution. Peripheral listen ganglion and vestibular ganglion ARIR highly expressed. NRG4 only expressed in mature cells of the pancreas, which showed low levels of expression in muscle cells.

neuromodulation B Receptor Agonist (NMBR) gestational age of pregnant rats and explore its impact mechanism

Observed neuromodulation B Receptor Agonist (NMBR) gestational age of pregnant rats and explore its impact mechanism. The establishment of accurate gestational age of pregnant mice model, randomized (n = 10). Pregnancy 18d2 6: 00pm, respectively, intraperitoneal injection of NMB (30,90,150 g kg-1), oxytocin (50mIU kg-1) and the volume of solvent, continuous 2d observation of pregnant rats of gestational age and birth interval. Pregnancy 18d6 8,10,12: 00am were given the above treatment, 4h after the last administration to take the pregnant rat uterine smooth muscle tissue, the use NoShift transcription factor analysis to detect the DNA binding activity of NF BP65, semi-quantitative RT PCR and Western blot detection of HSP70 of IL 6mRNA and protein expression. Results 150 gkg-1NMBR group gestational age was significantly shorter than in the control group and low dose group (P <0 05); NF BP65DNA combination of activity, HSP70, and of IL 6mRNA expression level was significantly higher (P <0 05). The conclusion NMBR agonists may be pregnant rat uterine smooth muscle NF the BP65 HSP70/IL 6 pathway to shorten gestational age.

Neuromodulation B Receptor (neuromedinB receptor, NMBR) is a mammalian bombesin (bombesin, BB) receptor family members, showed a significant difference in expression in uterine smooth muscle before and after the labor. The NMBR role in the onset of labor and the mechanism is unclear, but studies have shown that the NMBR upstream gene with neuroendocrine function, with G-protein coupled receptor (Gprotein coupled re ceptor, GPCR) structure of the downstream gene nuclear factor B (nuclearfactor {kappa} B NFB) is the hub of transcriptional activation of the cells within a variety of ways, and modulation of cytokines, the production of stress proteins, suggesting that the NMBR the basis of good contractions of drug targets. In this paper, the effects of different doses of NMBR agonists of pregnant

Mouse gestational age and birth interval, clear NMBR role in the delivery start; NFBP65DNA pregnant uterus smooth muscle cells through its binding activity of heat shock protein 70 (heat shockpro tein70, HSP70) and interleukin 6 (of interleukin 6, IL 6) mRNA and protein expression to explore the mechanism of the the NMBR influence of gestational age.

NRGs by six different domains: the amino-terminal region of the immunoglobulin-like domain

Neuromodulation prime NRGs by six different domains: the amino-terminal region of the immunoglobulin-like domain, EGF-like domain, the juxtamembrane sequence of the transmembrane sequence and cytoplasmic domain. The NRGs existence of different forms of soluble and membrane chimeric. Most of the the NRGs First synthesis and membrane-bound precursor proN RGs proNRGs followed to produce soluble NRGs, and secretion of this form. NRGs may play a role in cell paracrine autocrine form.

ErbBs receptors ErbBs receptors membrane receptor, its structure consists of an extracellular binding site domain, a transmembrane domain, a tyrosine kinase domain and a C-terminal domain. The ErbBs receptor subtypes may form homo-or heterodimer, dimer functions and constitute a dimer receptor subtypes to stimulate the ligand and is activated in the intracellular signal transduction pathways related

The pathophysiology of ischemic brain injury

Brain tissue ischemia and hypoxia may be due to a variety of mechanisms to activate the Erzhi brain edema and neuronal injury, and the resulting patient permanent disability and even death. Cerebral ischemia and hypoxia, microcirculation and cerebral ischemia after free radicals, arachidonic acid metabolites, excitatory amino acids and free fatty acids increased, resulting in severe vasogenic and cell-derived brain edema. Cerebral blood flow, vascular endothelial hypoxic injury and permeability increased destruction of blood-brain barrier function, resulting in secondary brain edema occurs when blood flow recanalization. The cerebral edema cerebral perfusion pressure changes and the enormous changes of the extracellular environment and further increase the brain tissue ischemia and hypoxia, and secondary apoptosis and inflammatory responses, forming a vicious cycle until the cell death.

In the middle cerebral artery occlusion and reperfusion (MCAO melon) model, starting with the glutamate-dependent, excitotoxic nerve damage. Hours is followed by cell death stage of infarct development to peripheral areas and the cerebral cortex when neuronal injury and apoptosis and inflammatory responses. Ischemia-induced neuronal damage response includes the following three mechanisms: ischemia-induced expression of IL-1pmRNA; ischemia-induced neuronal apoptosis; ischemia-induced glial reaction. Exacerbate neuronal death caused by the mechanism of apoptosis in the early stages of cell death caused by inflammation. Interleukin-1 (inierlukin a 1, IL-1) is the inflammation of early cytokines, is considered to be important factors controlling neuronal apoptosis induced by ischemic brain injury. One result of ischemia-mediated inflammatory response is the activation and infiltration of mononuclear cells, the cerebral cortex of macrophages / microglia infiltration and activation is a characteristic reaction of ischemic stroke-induced inflammation. Can be found in a large number of macrophages / microglia in the infarcted cerebral hemisphere contralateral but not MCAO rat brain cortex around the infarct area after 24h of glial fibrillary acidic protein (gelatinousfiberac remember Protein GEAp) immune response was significantly enhanced, suggesting the presence of astrocytes.