Neuregulins Regulate Cardiac Parasympathetic Activity

Okoshi, Katashi; Nakayama, Masaaki; Yan, Xinhua; Okoshi, Marina Politi; Schuldt, Adam J.T.; Marchionni, Mark A.; Lorell, Beverly H.

doi:10.1161/01.cir.0000138109.32748.80

Cited by 59 publications

(15 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ErbB4 is highly expressed during re-epithelialization of urothelium [40], and antiadrenergic NRG-1/ErbB signaling disappears when the muscarinic cholinergic receptor is blocked [41]. In addition, antiadrenergic muscarinic cholinergic signaling is diminished in the absence of NRG-1 [42]. Although the molecular mechanism underlying the cooperation between the NRG-1/ErbB system and the cholinergic system are still under investigation, NRG-1 may be related to the recycling and maintenance of urothelium and may act in a manner similar to a cholinergic receptor in the urothelium.…”

Section: Discussionmentioning

confidence: 99%

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

2013

View full text Add to dashboard Cite

BackgroundTo determine whether neuregulin-1(NRG-1) is a potential new biomarker of overactive bladder (OAB) induced by partial urethral obstruction in a rat model of OAB and to evaluate the urothelium as a therapeutic target of OAB.MethodsFemale Sprague–Dawley rats were separated into three 20-animal groups: normal, OAB, and 5-hydroxymethyl tolterodine (5-HMT)-treated OAB. In the OAB and OAB + 5-HMT groups, the urethra of each animal was partially obstructed; the OAB + 5-HMT group received intravenous 5-HMT for 3 weeks. At the conclusion of the 5-HMT dosing, the rats in each group underwent cystometrography, and the bladders were histologically evaluated. The expression of brain derived-neurotrophic factor (BDNF) and NRG-1 were evaluated in the urothelium.ResultsCompared with the control group, the OAB group showed a markedly increased bladder weight and a significant decrease in the micturition interval and volume; rats in the OAB + 5-HMT group showed decreased bladder weights and an improved micturition interval and volume. BDNF and NRG-1 were expressed at significantly higher levels in the OAB group, and were significantly reduced in the OAB + 5-HMT group compared with the control group.ConclusionsThe study suggests that NRG-1 is a potential new biomarker of OAB; the urothelium might be a therapeutic target for OAB treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

2013

View full text Add to dashboard Cite

show abstract

“…36 NRG-1β also regulates muscarinic cholinergic receptor expression and activity. 37 Whether these antiadrenergic effects account for the deleterious effects of trastuzumab on cardiac function are yet to be fully examined.…”

Section: Nrg-1/erbb Signaling In Adult Heart Structure and Functionmentioning

confidence: 99%

Neuregulin in Cardiovascular Development and Disease

Odiete

Hill

Sawyer

2012

Circulation Research

246

203

View full text Add to dashboard Cite

Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease.

show abstract

“…Indeed, antiadrenergic NRG-1/ErbB signaling disappears when muscarinic cholinergic receptor is blocked (Figure 2, left), 28 and antiadrenergic muscarinic cholinergic signaling is diminished in the absence of NRG-1. 29 Within this cooperation between the ErbB and muscarinic receptor signaling, adaptive regulation of NRG-1 synthesis and release from cardiac endothelial cells seem to be important. Indeed, synthesis and release of this factor are controlled, at least in part, by the activity of the adrenergic and renin-angiotensin systems.…”

Section: Interaction Between Nrg-1/erbb Signaling and The Neurohormonmentioning

confidence: 99%

Role of Neuregulin-1/ErbB Signaling in Cardiovascular Physiology and Disease

2007

View full text Add to dashboard Cite

Abstract-Since the discovery that neuregulin-1 (NRG-1)/ErbB signaling is indispensable in cardiac development, evidence has shown that this system also plays a crucial role in the adult heart. In patients, an inhibitory ErbB2 antibody, trastuzumab, used in the treatment of mammary carcinomas, increases the risk for the development of cardiotoxic cardiomyopathy. Postnatal disruption of NRG-1/ErbB signaling by gene targeting in mice leads to dilated cardiomyopathy. Initially, the search for the mechanisms behind these observations focused mainly on the effects of NRG-1 on cardiomyocyte growth and survival and revealed that NRG-1 has Akt-dependent antiapoptotic effects in cultured cardiomyocytes. In vivo studies, however, did not uniformly reinforce a role for apoptosis in the development of cardiomyopathy induced by impaired NRG-1/ErbB signaling. More recent studies have revealed that NRG-1 is involved in the regulation of cardiac sympathovagal balances by counterbalancing adrenergic stimulation of the adult myocardium and through an obligatory interaction with the muscarinic cholinergic system. NRG-1 is synthesized and released by the endocardial and cardiac microvascular endothelium, dynamically controlled by neurohormonal and biomechanical stimuli. The physiology of the cardiac NRG-1/ErbB system has implications for the treatment of both cancer and heart failure. Clinical studies in breast cancer with novel ErbB inhibitors are currently underway. Novel oncological indications for ErbB inhibition are emerging; cardiovascular side effects need to be carefully monitored. On the other hand, pharmacological activation of ErbB signaling is likely an unrecognized and beneficial effect of currently used drugs in heart failure and a promising therapeutic approach to prevent or reverse myocardial dysfunction. Key Words: endothelium Ⅲ receptors, ErbB-2 Ⅲ heart failure Ⅲ neuregulins N euregulin-1 (NRG-1) is a member of the epidermal growth factor (EGF) family known to activate proliferation, differentiation, and survival of many tissue types, including breast epithelial cells, glial cells, neurons, and myocytes. 1-4 Its biological effects are mediated by a set of tyrosine kinase receptors (ErbB2, ErbB3, and ErbB4) that dimerize on ligand binding, leading to phosphorylation and downstream signaling. 5 NRG-1 biology is complicated by the fact that multiple splice variants are produced from the NRG-1 gene (for review, see elsewhere 6 ). These NRG-1 isoforms can be divided into 3 types. Type I and II NRGs contain an immunoglobulin-like domain and are single-pass transmembrane proteins. Type III NRGs, containing a cysteine-rich domain, are 2-pass transmembrane proteins. Proteolytic cleavage of type I and II NRGs by members of the a-disintegrin and metalloprotease (ADAM) family such as tumor necrosis factor-␣ converting enzyme (ADAM17) and meltrin-␤ (ADAM19) 7,8 results in the release of a bioactive fragment. Cleavage of type III isoforms generates a transmembrane N-terminal fragment (Figure 1). 9 A common motif to all NRG isofo...

show abstract

Neuregulins Regulate Cardiac Parasympathetic Activity

Cited by 59 publications

References 46 publications

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

Changes of neuregulin-1(NRG-1) expression in a rat model of overactive bladder induced by partial urethral obstruction: is NRG-1 a new biomarker of overactive bladder?

Neuregulin in Cardiovascular Development and Disease

Role of Neuregulin-1/ErbB Signaling in Cardiovascular Physiology and Disease

Contact Info

Product

Resources

About