C-type natriuretic peptide is a Schwann cell-derived factor for development and function of sensory neurons

The plasma brain natriuretic peptide (BNP) level is increased in the acute phase of human stroke, but its source and function are unclear. Recently, we showed that the BNP level was higher in atherothrombotic cerebral infarction (69.1±9.4 pg/ml) than in control subjects (31.1±5.4 pg/ml), and that the BNP level in ischemic stroke was positively correlated with the NIH Stroke Scale (r=0.41, p<0.05) and infarct volume (r=0.34, p<0.05). Astrocytes provide metabolic and trophic support to neurons and modulate synaptic activities. At the early stage of brain ischemia, astrocytes are swollen, and their damage may compromise postischemic neuronal survival. We tested the hypothesis that human astrocytes produce BNP under hypoxia, and this endogenous BNP protects against apoptosis in an autocrine fashion. The human astrocyte cell line, U373MG, was exposed to hypoxia (O 2 ≤1%) for 24 hours. The ratio of BNP to GAPDH mRNA was increased by 7.7±.0 fold after 12-hour hypoxia and further increased by 8.6±1.6 fold after 24-hour hypoxia compared with that in 3-hour normoxia (both, p<0.01). The protein expression assessed by Western blot was increased by 2.0±0.4 fold at 24 hours (n=5, p<0.05). Tyrosine phosphorylation of c-Src was observed by 2.0±0.2-fold increase at 30 minutes. These responses to hypoxia were all blocked by pretreatment with PP1 at 50μM, an inhibitor of c-Src. Apoptosis was measured by detecting caspase activation by flow cytometry, and it was increased by 2.5±0.1 fold after 24-hour hypoxia compared with that in normoxia. To investigate the role of up-regulated BNP in apoptosis, we performed the loss of function test by transfecting a specific siRNA for NPPB that suppressed BNP by more than 80%. The activity of caspases in the BNP knockdown cells was increased by 3.2±0.2 fold after 24-hour hypoxia compared with that in normoxia (n=5, p<0.001), and it was greater than that in the cells transfected with non-targeting siRNA. These results indicate that hypoxia increases BNP gene expression through the c-Src-dependent signaling cascade in the human astrocytes. Endogenous BNP shows brain protection via the anti-apoptotic effect. BNP may be useful in the treatment of ischemic brain diseases.

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Abstract 19478: Endothelial and Cardiomyocyte -derived C-type Natriuretic Peptide Coordinate Heart Structure and Function

Circulation ◽

10.1161/circ.132.suppl_3.19478 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Amie J Moyes ◽

Sandy M Chu ◽

Reshma S Baliga ◽

Adrian J Hobbs

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Cardiac Function ◽

Infarct Size ◽

Natriuretic Peptide ◽

Vascular Tone ◽

Ex Vivo ◽

Pressure Overload ◽

Structure And Function ◽

And Function

Background: Endothelium-derived C-type natriuretic peptide (CNP) plays a key vascular homeostatic role governing vascular tone, blood pressure, leukocyte flux, platelet reactivity and the integrity of the vessel wall. However, relatively little is known about physiological role(s) for endogenous CNP in regulating cardiac structure and function. Herein, we have utilised novel mouse strains with endothelium or cardiomyocyte -specific deletion of CNP to determine if the peptide modulates heart function under basal conditions and during cardiac stress. Methods: Blood pressure and ECG were assessed by radiotelemetry. A Langendorff heart model was used to study coronary vascular reactivity and ischemia-reperfusion (I/R) injury ex vivo. Echocardiography was performed to determine cardiac function at baseline and following pressure overload (trans-aortic constriction; 6 weeks) -induced left ventricular hypertrophy/heart failure. Results: Hearts from endothelium-specific CNP knockout (ecCNP KO) mice exhibited smaller reductions in coronary perfusion pressure (CPP) compared to wildtype (WT) littermates in response to the vasodilators bradykinin (ΔCPP: WT=31.7±2.7%, KO=21.1±2.9%, n=8, p<0.05) and acetylcholine (ΔCPP: WT=36.4±4.4%, KO=18.5±3.8%, n=6, p<0.05). Shear-stress induced coronary dilatation (i.e. reactive hyperaemia) was also blunted in ecCNP KO hearts (AUC: WT=2804±280 [a.u.], KO=1493±280 [a.u.], n=8, p<0.05). Under basal conditions the heart rate (BPM: WT=605±5, KO 579±4, n=5, p<0.001) and contractility (QA interval; WT=13.7±0.1ms, KO=14.8±0.1ms, n=5, p<0.001) were significantly reduced in cardiomyocyte-specific CNP (cmCNP) KO mice compared to WT. Myocardial infarct size was larger in cmCNP KO following I/R injury ex vivo (Infarct size: WT=14.1±6.3%, KO=21.8±1.8 %, n=6, p<0.05). Furthermore, cmCNP KO mice exhibited greater cardiac dysfunction following pressure-overload (e.g. fractional shortening: WT=34.4±0.9%, KO=30.5±1.4%, n=8, p<0.05). Conclusion: These data suggest that CNP of endothelial and cardiomyocyte origin preserves cardiac function and morphology via the regulation of coronary vascular tone, heart rate, and myocardial contractility/hypertrophy.

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Role of Axonal Odorant Receptors in Olfactory Topography

Neuroscience Insights ◽

10.1177/2633105520923411 ◽

2020 ◽

Vol 15 ◽

pp. 263310552092341

Author(s):

Claudia Lodovichi

Keyword(s):

Olfactory Bulb ◽

Sensory Neurons ◽

Axon Terminal ◽

Internal Representation ◽

Dual Role ◽

Odorant Receptors ◽

Topographic Map ◽

And Function ◽

Guidance Molecule

A unique feature in the organization of the olfactory system is the dual role of the odorant receptors: they detect odors in the nasal epithelium and they play an instructive role in the convergence of olfactory sensory neuron axons in specific loci, ie, glomeruli, in the olfactory bulb. The dual role is corroborated by the expression of the odorant receptors in 2 specific locations of the olfactory sensory neurons: the cilia that protrude in the nostril, where the odorant receptors interact with odors, and the axon terminal, a suitable location for a potential axon guidance molecule. The mechanism of activation and function of the odorant receptors expressed at the axon terminal remained unknown for almost 20 years. A recent study identified the first putative ligand of the axonal odorant receptors, phosphatidylethanolamine-binding protein1, a molecule expressed in the olfactory bulb. The distinctive mechanisms of activation of the odorant receptors expressed at the opposite locations in sensory neurons, by odors, at the cilia, and by molecules expressed in the olfactory bulb, at the axon terminal, explain the dual role of the odorant receptors and link the specificity of odor perception with its internal representation, in the topographic map.

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