Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients' specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST.

The role of basophils in acquired protective immunity to tick infestation.

Ticks are blood-feeding ectoparasites that transmit a variety of pathogens to host animals and humans, causing severe infectious diseases such as Lyme disease. In a certain combination of animal and tick species, tick infestation elicits acquired immunity against ticks in the host, which can reduce the ability of ticks to feed on blood and to transmit pathogens in the following tick infestations. Therefore, our understanding of the cellular and molecular mechanisms of acquired tick resistance (ATR) can advance the development of anti-tick vaccines to prevent tick infestation and tick-borne diseases. Basophils are a minor population of white blood cells circulating in the bloodstream and are rarely observed in peripheral tissues under steady-state conditions. Basophils have been reported to accumulate at tick-feeding sites during re-infestation in cattle, rabbits, guinea pigs and mice. Selective ablation of basophils resulted in a loss of ATR in guinea pigs and mice, illuminating the essential role of basophils in the manifestation of ATR. In this review, we discuss the recent advance in the elucidation of the cellular and molecular mechanisms underlying basophil recruitment to the tick-feeding site and basophil-mediated ATR.

Sympathetic and parasympathetic innervation in cancer: therapeutic implications.

PURPOSE: The autonomic nervous system, consisting of sympathetic and parasympathetic/vagal nerves, is known to control the functions of any organ, maintaining whole-body homeostasis under physiological conditions. Recently, there has been increasing evidence linking sympathetic and parasympathetic/vagal nerves to cancers. The present review aimed to summarize recent developments from studies addressing the relationship between sympathetic and parasympathetic/vagal nerves and cancer behavior. METHODS: Literature review. RESULTS: Human and animal studies have revealed that sympathetic and parasympathetic/vagal nerves innervate the cancer microenvironment and alter cancer behavior. The sympathetic nerves have cancer-promoting effects on prostate cancer, breast cancer, and melanoma. On the other hand, while the parasympathetic/vagal nerves have cancer-promoting effects on prostate, gastric, and colorectal cancers, they have cancer-suppressing effects on breast and pancreatic cancers. These neural effects may be mediated by ß-adrenergic or muscarinic receptors and can be explained by changes in cancer cell behavior, angiogenesis, tumor-associated macrophages, and adaptive antitumor immunity. CONCLUSIONS: Sympathetic nerves innervating the tumor microenvironment promote cancer progression and are related to stress-induced cancer behavior. The parasympathetic/vagal nerves have variable (promoting or suppressing) effects on different cancer types. Approaches directed toward the sympathetic and parasympathetic/vagal nerves can be developed as a new cancer therapy. In addition to existing pharmacological, surgical, and electrical approaches, a recently developed virus vector-based genetic local neuroengineering technology is a powerful approach that selectively manipulates specific types of nerve fibers innervating the cancer microenvironment and leads to the suppression of cancer progression. This technology will enable the creation of "cancer neural therapy" individually tailored to different cancer types.

Tonic aortic depressor nerve stimulation does not impede baroreflex dynamic characteristics concomitantly mediated by the stimulated nerve.

Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

Aortic depressor nerve stimulation does not impede the dynamic characteristics of the carotid sinus baroreflex in normotensive or spontaneously hypertensive rats.

Recent clinical trials in patients with drug-resistant hypertension indicate that electrical activation of the carotid sinus baroreflex can reduce arterial pressure (AP) for more than a year. To examine whether the electrical stimulation from one baroreflex system impedes normal short-term AP regulation via another unstimulated baroreflex system, we electrically stimulated the left aortic depressor nerve (ADN) while estimating the dynamic characteristics of the carotid sinus baroreflex in anesthetized normotensive Wistar-Kyoto (WKY; n = 8) rats and spontaneously hypertensive rats (SHR; n = 7). Isolated carotid sinus regions were perturbed for 20 min using a Gaussian white noise signal with a mean of 120 mmHg for WKY and 160 mmHg for SHR. Tonic ADN stimulation (2 Hz, 10 V, and 0.1-ms pulse width) decreased mean sympathetic nerve activity (73.4 ± 14.0 vs. 51.6 ± 11.3 arbitrary units in WKY, P = 0.012; and 248.7 ± 33.9 vs. 181.1 ± 16.6 arbitrary units in SHR, P = 0.018) and mean AP (90.8 ± 6.6 vs. 81.2 ± 5.4 mmHg in WKY, P = 0.004; and 128.6 ± 9.8 vs. 114.7 ± 10.3 mmHg in SHR, P = 0.009). The slope of dynamic gain in the neural arc transfer function from carotid sinus pressure to sympathetic nerve activity was not different between trials with and without the ADN stimulation (12.55 ± 0.93 vs. 13.03 ± 1.28 dB/decade in WKY, P = 0.542; and 17.37 ± 1.01 vs. 17.47 ± 1.64 dB/decade in SHR, P = 0.946). These results indicate that the tonic ADN stimulation does not significantly modify the dynamic characteristics of the carotid sinus baroreflex.

Hybrid stage I palliation for hypoplastic left heart syndrome has no advantage on ventricular energetics: a theoretical analysis.

A hybrid procedure combining bilateral pulmonary artery banding with ductal stenting has recently been used as stage I palliation for hypoplastic left heart syndrome. However, the advantage of the hybrid procedure over the Norwood procedure on ventricular energetics remains unclear. To clarify this, we performed a computational analysis with a combination of time-varying elastance chamber model and modified three-element Windkessel vascular model. Although mean pulmonary artery (PA) pressure, pulmonary flow, and oxygen saturation were almost equivalent with the Norwood procedure, the hybrid procedure delivered higher systolic and lower diastolic systemic arterial pressures compared to the Norwood procedure with right ventricle (RV) to PA shunt. As a result, the hybrid procedure yielded increased systolic pressure-volume area and impaired mechanical efficiency. Therefore, the hybrid procedure has probably no advantage on ventricular energetics compared to the Norwood procedure with a RV-PA shunt.

Predominant role of neural arc in sympathetic baroreflex resetting of spontaneously hypertensive rats.

BACKGROUND: There is ongoing controversy over whether neural or peripheral factors are the predominant cause of hypertension. The closed-loop negative feedback operation of the arterial baroreflex hampers understanding of how arterial pressure (AP) is determined through the interaction between neural and peripheral factors. METHODS AND RESULTS: A novel analysis of an isolated open-loop baroreceptor preparation to examine sympathetic nervous activity (SNA) and AP responses to changes in carotid sinus pressure (CSP) in adult spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) was conducted. In the neural arc (CSP-SNA relationship), the midpoint pressure (128.9±3.8 vs. 157.9±8.1 mmHg, P<0.001) and the response range of SNA to CSP (90.5±3.7 vs. 115.4±7.6%/mmHg, P=0.011) were higher in SHR. In the peripheral arc (SNA-AP relationship), slope and intercept did not differ. A baroreflex equilibrium diagram was obtained by depicting neural and peripheral arcs in a pressure-SNA plane with rescaled SNA (% in WKY). The operating-point AP (111.3±4.4 vs. 145.9±5.2 mmHg, P<0.001) and SNA (90.8±3.2 vs. 125.1±6.9% in WKY, P<0.001) were shifted towards a higher level in SHR. CONCLUSIONS: The shift of the neural arc towards a higher SNA range indicated a predominant contribution to baroreflex resetting in SHR. Notwithstanding the resetting, the carotid sinus baroreflex in SHR preserved an ability to reduce AP if activated with a high enough pressure.

Medetomidine suppresses cardiac and gastric sympathetic nerve activities but selectively activates cardiac vagus nerve.

BACKGROUND: To identify a pharmacological agent that can selectively activate cardiac vagus nerve for potential use in vagal activation therapy against heart failure, the effects of medetomidine on autonomic nerve activities in both the heart and stomach were examined. METHODS AND RESULTS: In anesthetized rabbits, microdialysis probes were implanted into both the right atrial and gastric walls. Dialysate acetylcholine (ACh) and norepinephrine (NE) concentrations were measured by high-performance liquid chromatography. First, the effects of 100µg/kg of intravenous medetomidine on vagal ACh and sympathetic NE releases were examined. Medetomidine significantly increased cardiac ACh release (4.7±1.1 to 7.8±0.9nmol/L, P<0.05), but suppressed gastric ACh release (8.0±2.6 to 3.5±1.5nmol/L, P<0.01). In contrast, medetomidine suppressed both cardiac and gastric NE releases. Second, the effects of medetomidine on ACh releases induced by electrical vagus nerve stimulation (VNS; 10Hz) were examined. Electrical VNS significantly increased both cardiac (6.7±1.2 to 14.8±1.8nmol/L, P<0.01) and gastric (3.8±0.8 to 181.3±65.6nmol/L, P<0.01) ACh releases. Medetomidine did not alter the VNS-induced increases in ACh release. CONCLUSIONS: Medetomidine suppresses both cardiac and gastric sympathetic nerve activities. In contrast, medetomidine activates cardiac vagus nerve but inhibits gastric vagal activity. Medetomidine might be one of the potential pharmacological agents for vagal activation therapy against heart failure without the risk of gastric adverse effects.

Medetomidine, an α(2)-adrenergic agonist, activates cardiac vagal nerve through modulation of baroreflex control.

BACKGROUND: Although α(2)-adrenergic agonists have been reported to induce a vagal-dominant condition through suppression of sympathetic nerve activity, there is little direct evidence that they directly increase cardiac vagal nerve activity. Using a cardiac microdialysis technique, we investigated the effects of medetomidine, an α(2)-adrenergic agonist, on norepinephrine (NE) and acetylcholine (ACh) release from cardiac nerve endings. METHODS AND RESULTS: A microdialysis probe was implanted into the right atrial wall near the sinoatrial node in anesthetized rabbits and perfused with Ringer's solution containing eserine. Dialysate NE and ACh concentrations were measured using high-performance liquid chromatography. Both 10 and 100µg/kg of intravenous medetomidine significantly decreased mean blood pressure (BP) and the dialysate NE concentration, but only 100µg/kg of medetomidine enhanced ACh release. Combined administration of medetomidine and phenylephrine maintained mean BP at baseline level, and augmented the medetomidine-induced ACh release. When we varied the mean BP using intravenous administration of phenylephrine, treatment with medetomidine significantly steepened the slope of the regression line between mean BP and log ACh concentration. CONCLUSIONS: Medetomidine increased ACh release from cardiac vagal nerve endings and augmented baroreflex control of vagal nerve activity.

Adaptation of the respiratory controller contributes to the attenuation of exercise hyperpnea in endurance-trained athletes.

We have reported that minute ventilation [[Formula: see text]] and end-tidal CO(2) tension [[Formula: see text]] are determined by the interaction between central controller and peripheral plant properties. During exercise, the controller curve shifts upward with unchanged central chemoreflex threshold to compensate for the plant curve shift accompanying increased metabolism. This effectively stabilizes [Formula: see text] within the normal range at the expense of exercise hyperpnea. In the present study, we investigated how endurance-trained athletes reduce this exercise hyperpnea. Nine exercise-trained and seven untrained healthy males were studied. To characterize the controller, we induced hypercapnia by changing the inspiratory CO(2) fraction with a background of hyperoxia and measured the linear [Formula: see text] relation [[Formula: see text]]. To characterize the plant, we instructed the subjects to alter [Formula: see text] voluntarily and measured the hyperbolic [Formula: see text] relation ([Formula: see text]). We characterized these relations both at rest and during light exercise. Regular exercise training did not affect the characteristics of either controller or plant at rest. Exercise stimulus increased the controller gain (S) both in untrained and trained subjects. On the other hand, the [Formula: see text]-intercept (B) during exercise was greater in trained than in untrained subjects, indicating that exercise-induced upward shift of the controller property was less in trained than in untrained subjects. The results suggest that the additive exercise drive to breathe was less in trained subjects, without necessarily a change in central chemoreflex threshold. The hyperbolic plant property shifted rightward and upward during exercise as predicted by increased metabolism, with little difference between two groups. The [Formula: see text] during exercise in trained subjects was 21% lower than that in untrained subjects (P < 0.01). These results indicate that an adaptation of the controller, but not that of plant, contributes to the attenuation of exercise hyperpnea at an iso-metabolic rate in trained subjects. However, whether training induces changes in neural drive originating from the central nervous system, afferents from the working limbs, or afferents from the heart, which is additive to the chemoreflex drive to breathe, cannot be determined from these results.

Closed-loop spontaneous baroreflex transfer function is inappropriate for system identification of neural arc but partly accurate for peripheral arc: predictability analysis.

Although the dynamic characteristics of the baroreflex system have been described by baroreflex transfer functions obtained from open-loop analysis, the predictability of time-series output dynamics from input signals, which should confirm the accuracy of system identification, remains to be elucidated. Moreover, despite theoretical concerns over closed-loop system identification, the accuracy and the predictability of the closed-loop spontaneous baroreflex transfer function have not been evaluated compared with the open-loop transfer function. Using urethane and α-chloralose anaesthetized, vagotomized and aortic-denervated rabbits (n = 10), we identified open-loop baroreflex transfer functions by recording renal sympathetic nerve activity (SNA) while varying the vascularly isolated intracarotid sinus pressure (CSP) according to a binary random (white-noise) sequence (operating pressure ± 20 mmHg), and using a simplified equation to calculate closed-loop-spontaneous baroreflex transfer function while matching CSP with systemic arterial pressure (AP). Our results showed that the open-loop baroreflex transfer functions for the neural and peripheral arcs predicted the time-series SNA and AP outputs from measured CSP and SNA inputs, with r2 of 0.8 ± 0.1 and 0.8 ± 0.1, respectively. In contrast, the closed-loop-spontaneous baroreflex transfer function for the neural arc was markedly different from the open-loop transfer function (enhanced gain increase and a phase lead), and did not predict the time-series SNA dynamics (r2; 0.1 ± 0.1). However, the closed-loop-spontaneous baroreflex transfer function of the peripheral arc partially matched the open-loop transfer function in gain and phase functions, and had limited but reasonable predictability of the time-series AP dynamics (r2, 0.7 ± 0.1). A numerical simulation suggested that a noise predominantly in the neural arc under resting conditions might be a possible mechanism responsible for our findings. Furthermore, the predictabilities of the neural arc transfer functions obtained in open-loop and closed-loop conditions were validated by closed-loop pharmacological (phenylephrine and nitroprusside infusions) pressure interventions. Time-series SNA responses to drug-induced AP changes predicted by the open-loop transfer function matched closely the measured responses (r2, 0.9 ± 0.1), whereas SNA responses predicted by closed-loop-spontaneous transfer function deviated greatly and were the inverse of measured responses (r, −0.8 ± 0.2). These results indicate that although the spontaneous baroreflex transfer function obtained by closed-loop analysis has been believed to represent the neural arc function, it is inappropriate for system identification of the neural arc but is essentially appropriate for the peripheral arc under resting conditions, when compared with open-loop analysis.

Dynamic characteristics of baroreflex neural and peripheral arcs are preserved in spontaneously hypertensive rats.

Although baroreceptors are known to reset to operate in a higher pressure range in spontaneously hypertensive rats (SHR), the total profile of dynamic arterial pressure (AP) regulation remains to be clarified. We estimated open-loop transfer functions of the carotid sinus baroreflex in SHR and Wistar Kyoto (WKY) rats. Mean input pressures were set at 120 (WKY120 and SHR120) and 160 mmHg (SHR160). The neural arc transfer function from carotid sinus pressure to efferent splanchnic sympathetic nerve activity (SNA) revealed derivative characteristics in both WKY and SHR. The slope of dynamic gain (in decibels per decade) between 0.1 and 1 Hz was not different between WKY120 (10.1 ± 1.0) and SHR120 (10.4 ± 1.1) but was significantly greater in SHR160 (13.2 ± 0.8, P < 0.05 with Bonferroni correction) than in SHR120. The peripheral arc transfer function from SNA to AP showed low-pass characteristics. The slope of dynamic gain (in decibels per decade) did not differ between WKY120 (-34.0 ± 1.2) and SHR120 (-31.4 ± 1.0) or between SHR120 and SHR160 (-32.8 ± 1.3). The total baroreflex showed low-pass characteristics and the dynamic gain at 0.01 Hz did not differ between WKY120 (0.91 ± 0.08) and SHR120 (0.84 ± 0.13) or between SHR120 and SHR160 (0.83 ± 0.11). In both WKY and SHR, the declining slope of dynamic gain was significantly gentler for the total baroreflex than for the peripheral arc, suggesting improved dynamic AP response in the total baroreflex. In conclusion, the dynamic characteristics of AP regulation by the carotid sinus baroreflex were well preserved in SHR despite significantly higher mean AP.

Exercise training augments the dynamic heart rate response to vagal but not sympathetic stimulation in rats.

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 ± 1.5 vs. 4.5 ± 1.5 beats·min(-1)·Hz(-1); natural frequency, 0.07 ± 0.01 vs. 0.08 ± 0.01 Hz; damping coefficient, 1.96 ± 0.55 vs. 1.69 ± 0.15; and lag time, 0.7 ± 0.1 vs. 0.6 ± 0.1 s; sedentary vs. exercise trained, respectively, means ± SD). The transfer gain from vagal stimulation to HR response was 6.1 ± 3.0 in the sedentary and 9.7 ± 5.1 beats·min(-1)·Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 ± 0.05 vs. 0.17 ± 0.09 Hz) and lag time (0.1 ± 0.1 vs. 0.2 ± 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.

Corrigendum: Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control.

[This corrects the article DOI: 10.3389/fendo.2021.727915.].

Corrigendum: Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control.

[This corrects the article DOI: 10.3389/fendo.2021.727915.].

Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control.

In obesity and type 2 diabetes, numerous genes are differentially expressed, and microRNAs are involved in transcriptional regulation of target mRNAs, but miRNAs critically involved in the appetite control are not known. Here, we identified upregulation of miR-342-3p and its host gene Evl in brain and adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir342 (-/-) mice fed with HFHS chow were protected from obesity and diabetes. The hypothalamic arcuate nucleus neurons co-express Mir342 and EVL. The percentage of activated NPY+pSTAT3+ neurons were reduced, while POMC+pSTAT3+ neurons increased in Mir342 (-/-) mice, and they demonstrated the reduction of food intake and amelioration of metabolic phenotypes. Snap25 was identified as a major target gene of miR-342-3p and the reduced expression of Snap25 may link to functional impairment hypothalamic neurons and excess of food intake. The inhibition of miR-342-3p may be a potential candidate for miRNA-based therapy.

Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration.

Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling.

Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1beta (NRG-1beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.

Parallel resetting of arterial baroreflex control of renal and cardiac sympathetic nerve activities during upright tilt in rabbits.

Since humans are under ceaseless orthostatic stress, the mechanisms to maintain arterial pressure (AP) against gravitational fluid shift are important. As one mechanism, it was reported that upright tilt reset baroreflex control of renal sympathetic nerve activity (SNA) to a higher SNA in anesthetized rabbits. In the present study, we tested the hypothesis that upright tilt causes a parallel resetting of baroreflex control of renal and cardiac SNAs in anesthetized rabbits. In anesthetized rabbits (n = 8, vagotomized and aortic denervated) with 0 degrees supine and 60 degrees upright tilt postures, renal and cardiac SNAs were simultaneously recorded while isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg. Upright tilt shifted the reverse-sigmoidal curve of the CSP-SNA relationship to higher SNA similarly in renal and cardiac SNAs. Although upright tilt increased the maximal gain, the response range and the minimum value of SNA, the curves were almost superimposable in these SNAs regardless of postures. Scatter plotting of cardiac SNA over renal SNA during the stepwise changes in CSP was close to the line of identity in 0 degrees supine and 60 degrees upright tilt postures. In addition, upright tilt also shifted the reverse-sigmoidal curve of the CSP-heart rate relationship to a higher heart rate, with increases in the maximal gain and the response range. In conclusion, upright posture caused a resetting of arterial baroreflex control of SNA similarly in renal and cardiac SNAs in anesthetized rabbits.