Neuregulin-1/ErbB signaling in rostral ventrolateral medulla is involved in blood pressure regulation as an antihypertensive system

Matsukawa, Ryuichi; Hirooka, Yoshitaka; Nishihara, Masaaki; Izutsu, Koji; Sunagawa, Kenji

doi:10.1097/hjh.0b013e32834937d6

Cited by 27 publications

(25 citation statements)

References 35 publications

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“…Since both the nervous system and the breast gland express NRG1 receptors in adults, these organs may show side effects. Injection of NRG1 and ErbB receptor antagonists into the rostral ventrolateral medulla, an important region involved in central cardiovascular regulation, affected heart rate and blood pressure (61). Although it is unknown whether NRG1 administered by injection into the peritoneum or blood stream is able to cross the blood-brain barrier, these findings and the association between ErbB signaling and mental disorders (15) suggest the potential for side effects on the nervous system.…”

Section: Effects Of Nrg1 Administration Outside Of the Heartmentioning

confidence: 99%

The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

Wadugu

Kühn

2012

American Journal of Physiology-Heart and Circulatory Physiology

113

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Wadugu B, Kühn B. The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation. Am J Physiol Heart Circ Physiol 302: H2139 -H2147, 2012. First published March 16, 2012 doi:10.1152/ajpheart.00063.2012.-The signaling complex consisting of the growth factor neuregulin-1 (NRG1) and its tyrosine kinase receptors ErbB2 and ErbB4 has a critical role in cardiac development and homeostasis of the structure and function of the adult heart. Recent research results suggest that targeting this signaling complex may provide a viable strategy for treating heart failure. Clinical trials are currently evaluating the effectiveness and safety of intravenous administration of recombinant NRG1 formulations in heart failure patients. Endogenous as well as administered NRG1 has multiple possible activities in the adult heart, but how these are related is unknown. It has recently been demonstrated that NRG1 administration can stimulate proliferation of cardiomyocytes, which may contribute to repair failing hearts. This review summarizes the current knowledge of how NRG1 and its receptors control cardiac physiology and biology, with special emphasis on its role in cardiomyocyte proliferation during myocardial growth and regeneration. cardiac repair; cardiac regeneration; cardiomyocyte differentiation THIS ARTICLE is part of a collection on Physiological Basis of Cardiovascular Cell and Gene Therapies. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology. org/.

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Section: Effects Of Nrg1 Administration Outside Of the Heartmentioning

confidence: 99%

The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

Wadugu

Kühn

2012

American Journal of Physiology-Heart and Circulatory Physiology

113

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“…A pair of stainless steel bipolar electrodes was placed beneath the renal nerve to record multifiber RSNA. 25 All signals were recorded on a computer using a PowerLab system (AD Instruments, Nagoya, Japan). The signal from the electrodes was amplified, passed through a band pass filter and then rectified and integrated (resetting every 0.1 s).…”

Section: Animals and General Proceduresmentioning

confidence: 99%

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

et al. 2012

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Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na + -rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serumand glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na + -rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na + -rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

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“…99 We recently found that neuregulin-1/ErbB signaling in the RVLM may contribute to the neural mechanisms of hypertension. 100 Furthermore, neuregulin-1/ErbB signaling in the RVLM may increase NO synthesis and γ-aminobutyric acid activity, thereby decreasing sympathetic activity. 101 This is one of aspect of neuregulin-1/ErbB signaling.…”

Section: Molecular Target Drugs and Hypertensionmentioning

confidence: 99%

Potential Clinical Application of Recently Discovered Brain Mechanisms Involved in Hypertension

et al. 2013

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A ccumulating evidence indicates that central activation of the sympathetic nervous system plays an important role in hypertension. [1][2][3][4][5][6][7][8] The aim of this review is to inform clinicians about the involvement of brain mechanisms in clinical hypertension and the applicability of recent findings to clinical practice. Clinicians, particularly cardiologists and nephrologists, are now initiating clinical treatment of hypertension that targets the sympathetic nervous system using novel techniques, such as catheter-based renal denervation and carotid baroreflex activation therapy.9,10 Renal denervation reduces efferent renal sympathetic activity, thereby decreasing renal tubular sodium reabsorption, supporting renal blood flow, and inhibiting the renin-angiotensin-aldosterone system, which has a blood pressure-lowering effect. In addition, it has been proposed that inhibition of central sympathetic outflow via reduced renal afferent input to the brain leads to a long-term reduction in blood pressure.11 Carotid baroreflex activation therapy reduces blood pressure and central sympathetic outflow, and the sympathoinhibitory action lasts for a much longer period than previously thought, without rapid adaptation. 12,13 In addition, the currently used antihypertensive drugs are suggested to act on the central nervous system. 7,14 Neural Mechanisms Are Re-Emerging as a Pathogenesis and Pathophysiology of HypertensionThe brain is essential for processing and integrating various stimuli from the periphery to maintain blood pressure and fluid homeostasis. 1-3 The circumventricular organs, hypothalamus, and brain stem are major brain regions contributing to this function.2 During the past several decades, however, neural mechanisms, such as arterial baroreflex function, have been considered to be involved in short-term blood pressure regulation, but not in long-term blood pressure control (ie, hypertension).1-4 Arterial baroreceptors adapt and thus cannot provide accurate negative feedback signals to the brain to maintain normal arterial pressure. Importantly, surgical removal of the afferent projections of arterial baroreceptors (sinoaortic denervation) results in a transient increase in arterial pressure but does not lead to chronic hypertension.2 These findings suggest that the renin-angiotensin system and kidney are major contributors to the pathogenesis of hypertension. 1,3,4 Several important series of studies revealed that arterial baroreflexes have a role in long-term blood pressure regulation. First, Thrasher 15 produced chronic unloading of arterial baroreceptors in dogs, in which 1 carotid sinus and the aortic depressor nerve were cut, and the carotid sinus from the remaining innervated region was isolated from the systemic arterial pressure. Baroreceptor unloading was then induced by ligating the common carotid artery proximal to the innervated sinus, which led to an increase in arterial pressure that lasted for several weeks; although the initial increase in arterial pressure was not sustained, the l...

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Neuregulin-1/ErbB signaling in rostral ventrolateral medulla is involved in blood pressure regulation as an antihypertensive system

Abstract: Our findings indicate that the NRG-1/ErbB signaling in the RVLM has depressor and sympathoinhibitory effects. Reduced NRG/ErbB2 signaling in the RVLM may contribute to the neural mechanisms of hypertension.

Cited by 27 publications

References 35 publications

The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

Potential Clinical Application of Recently Discovered Brain Mechanisms Involved in Hypertension

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