Top

Published in:

01-03-2014 | Pharmacologic Therapy (WHW Tang, Section Editor)

Neuregulin as a Heart Failure Therapy and Mediator of Reverse Remodeling

Authors: Cristi L. Galindo, Sergey Ryzhov, Douglas B. Sawyer

Published in: Current Heart Failure Reports | Issue 1/2014

Abstract

The beta isoform of Neuregulin-1 (NRG-1β), along with its receptors (ErbB2–4), is required for cardiac development. NRG-1β, as well as the ErbB2 and ErbB4 receptors, is also essential for maintenance of adult heart function. These observations have led to its evaluation as a therapeutic for heart failure. Animal studies and ongoing clinical trials have demonstrated beneficial effects of two forms of recombinant NRG-1β on cardiac function. In addition to the possible role for recombinant NRG-1βs as heart failure therapies, endogenous NRG-1β/ErbB signaling appears to play a role in restoring cardiac function after injury. The potential mechanisms by which NRG-1β may act as both a therapy and a mediator of reverse remodeling remain incompletely understood. In addition to direct effects on cardiac myocytes NRG-1β acts on the vasculature, interstitium, cardiac fibroblasts, and hematopoietic and immune cells, which, collectively, may contribute to NRG-1β’s role in maintaining cardiac structure and function, as well as mediating reverse remodeling.

Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995;378:386–90.PubMed

Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003;284:14–30.PubMed

Fleck D, Garratt AN, Haass C, Willem M. BACE1 dependent neuregulin processing: review. Curr Alzheimer Res. 2012;9:178–83.PubMed

Fleck D, van Bebber F, Colombo A, Galante C, Schwenk BM, Rabe L, et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci. 2013;33:7856–69.PubMed

Mendes-Ferreira P, De Keulenaer GW, Leite-Moreira AF, Bras-Silva C. Therapeutic potential of neuregulin-1 in cardiovascular disease. Drug Discov Today. 2013;18:836–42.PubMed

Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res. 2012;111:1376–85.PubMedCentralPubMed

Fukazawa R, Miller TA, Kuramochi Y, Frantz S, Kim YD, Marchionni MA, et al. Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. J Mol Cell Cardiol. 2003;35:1473–9.PubMed

Chen M, Bi LL, Wang ZQ, Zhao F, Gan XD, Wang YG. Time-dependent regulation of neuregulin-1beta/ErbB/ERK pathways in cardiac differentiation of mouse embryonic stem cells. Mol Cell Biochem. 2013;380:67–72.PubMed

Adam L, Vadlamudi R, Kondapaka SB, Chernoff J, Mendelsohn J, Kumar R. Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. J Biol Chem. 1998;273:28238–46.PubMed

10.

Clement CM, Thomas LK, Mou Y, Croslan DR, Gibbons GH, Ford BD. Neuregulin-1 attenuates neointimal formation following vascular injury and inhibits the proliferation of vascular smooth muscle cells. J Vasc Res. 2007;44:303–12.PubMed

11.

Russell KS, Stern DF, Polverini PJ, Bender JR. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis. Am J Physiol. 1999;277:H2205–11.PubMed

12.

Timolati F, Ott D, Pentassuglia L, Giraud MN, Perriard JC, Suter TM, et al. Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol. 2006;41:845–54.PubMed

13.

Fukazawa T, Matsumoto M, Imura T, Khalesi E, Kajiume T, Kawahara Y, et al. Electrical stimulation accelerates neuromuscular junction formation through ADAM19/neuregulin/ErbB signaling in vitro. Neurosci Lett. 2013;545:29–34.PubMed

14.

Kasasbeh, E., Murphy, A., Ahmad, F.A., Tu, E., Williams, P., Nunnally, A., et al. Neuregulin-1β improves cardiac remodeling after myocardial infarction in swine. Circulation. 2011;124:Abstract 15531.

15.

Pentassuglia L, Sawyer DB. ErbB/integrin signaling interactions in regulation of myocardial cell-cell and cell-matrix interactions. Biochim Biophys Acta. 2013;1833:909–16.PubMed

16.

Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105:1551–4.PubMed

17.

Baliga RR, Pimental DR, Zhao YY, Simmons WW, Marchionni MA, Sawyer DB, et al. NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK. Am J Physiol. 1999;277:H2026–37.PubMed

18.

Kuramochi Y, Cote GM, Guo X, Lebrasseur NK, Cui L, Liao R, et al. Cardiac endothelial cells regulate reactive oxygen species-induced cardiomyocyte apoptosis through neuregulin-1beta/erbB4 signaling. J Biol Chem. 2004;279:51141–7.PubMed

19.

Zhao YY, Sawyer DB, Baliga RR, Opel DJ, Han X, Marchionni MA, et al. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem. 1998;273:10261–9.PubMed

20.

Kuramochi Y, Guo X, Sawyer DB. Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes. J Mol Cell Cardiol. 2006;41:228–35.PubMedCentralPubMed

21.

Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW. Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation. 2004;109:324–6.PubMed

22.

Brero A, Ramella R, Fitou A, Dati C, Alloatti G, Gallo MP, et al. Neuregulin-1beta1 rapidly modulates nitric oxide synthesis and calcium handling in rat cardiomyocytes. Cardiovasc Res. 2010;88:443–52.PubMed

23.

•• Ebner B, Lange SA, Eckert T, Wischniowski C, Ebner A, Braun-Dullaeus RC, et al. Uncoupled eNOS annihilates neuregulin-1beta-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction. Mol Cell Biochem. 2013;373:115–23. This study made the interesting observation that NRG administered during ischemia and prior to reperfusion increases infarct size. It went on to show that this effect is due to enhancing ROS formation by activating uncoupled nitric oxide synthase (NOS). Either removing eNOS or improving coupling through coadministration of L-arginine as a substrate for eNOS converted NRG to a cardioprotective lingand, likely through GSK3β inactivation.PubMed

24.

Gu X, Liu X, Xu D, Li X, Yan M, Qi Y, et al. Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin. Cardiovasc Res. 2010;88:334–43.PubMed

25.

26.

Cote GM, Miller TA, Lebrasseur NK, Kuramochi Y, Sawyer DB. Neuregulin-1alpha and beta isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro. Exp Cell Res. 2005;311:135–46.PubMed

27.

Lebrasseur NK, Cote GM, Miller TA, Fielding RA, Sawyer DB. Regulation of neuregulin/ErbB signaling by contractile activity in skeletal muscle. Am J Physiol Cell Physiol. 2003;284:C1149–55.PubMed

28.

Xu Z, Ford GD, Croslan DR, Jiang J, Gates A, Allen R, et al. Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. Neurobiol Dis. 2005;19:461–70.PubMed

29.

Shyu WC, Lin SZ, Chiang MF, Yang HI, Thajeb P, Li H. Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging. 2004;25:935–44.PubMed

30.

Xu Z, Jiang J, Ford G, Ford BD. Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke. Biochem Biophys Res Commun. 2004;322:440–6.PubMed

31.

• Hedhli N, Dobrucki LW, Kalinowski A, Zhuang ZW, Wu X, Russell 3rd RR, et al. Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis. Cardiovasc Res. 2012;93:516–24. These investigators defined a role for endothelial-derived NRG as an important mediator of ischemia-induced angiogenesis in peripheral vascular disease. These findings have clear therapeutic implications that have yet to be explored.PubMed

32.

•• Hedhli N, Huang Q, Kalinowski A, Palmeri M, Hu X, Russell RR, et al. Endothelium-derived neuregulin protects the heart against ischemic injury. Circulation. 2011;123:2254–62. These investigators used endothelial-specific ablation of NRG to demonstrate a role for endogenous cardiac NRG in the protection of the heart from ischemic injury. The elegant work sets the stage to explore how endogenous and exogenous recombinant neuregulin might be used to enhance recovery from myocardial infarction.PubMedCentralPubMed

33.

Pentassuglia L, Graf M, Lane H, Kuramochi Y, Cote G, Timolati F, et al. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res. 2009;315:1302–12.PubMed

34.

Fang SJ, Wu XS, Han ZH, Zhang XX, Wang CM, Li XY, et al. Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Chin Med J (Engl). 2010;123:3597–604.

35.

Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA, et al. Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation. 1999;100:407–12.PubMed

36.

Gui C, Zhu L, Hu M, Lei L, Long Q. Neuregulin-1/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy. Cardiovasc Pathol. 2012;21:414–20.PubMed

37.

Rohrbach S, Niemann B, Silber RE, Holtz J. Neuregulin receptors erbB2 and erbB4 in failing human myocardium – depressed expression and attenuated activation. Basic Res Cardiol. 2005;100:240–9.PubMed

38.

Peng X, Guo X, Borkan SC, Bharti A, Kuramochi Y, Calderwood S, et al. Heat shock protein 90 stabilization of ErbB2 expression is disrupted by ATP depletion in myocytes. J Biol Chem. 2005;280:13148–52.PubMed

39.

Geisberg C, Pentassuglia L, Sawyer DB. Cardiac side effects of anticancer treatments: new mechanistic insights. Curr Heart Fail Rep. 2012;9:211–8.PubMedCentralPubMed

40.

Seshadri R, Matthews C, Dobrovic A, Horsfall DJ. The significance of oncogene amplification in primary breast cancer. Int J Cancer. 1989;43:270–2.PubMed

41.

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.PubMed

42.

Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215–21.PubMed

43.

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.PubMed

44.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.PubMed

45.

Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol. 2007;25:3859–65.PubMed

46.

Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009;100:684–92.PubMedCentralPubMed

47.

Davis M, Witteles RM. Cardiac testing to manage cardiovascular risk in cancer patients. Semin Oncol. 2013;40:147–55.PubMed

48.

Liu X, Gu X, Li Z, Li X, Li H, Chang J, et al. Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy. J Am Coll Cardiol. 2006;48:1438–47.PubMed

49.

Bersell K, Arab S, Haring B, Kuhn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell. 2009;138:257–70.PubMed

50.

Bian Y, Sun M, Silver M, Ho KK, Marchionni MA, Caggiano AO, et al. Neuregulin-1 attenuated doxorubicin-induced decrease in cardiac troponins. Am J Physiol Heart Circ Physiol. 2009;297:H1974–83.PubMed

51.

Guo YF, Zhang XX, Liu Y, Duan HY, Jie BZ, Wu XS. Neuregulin-1 attenuates mitochondrial dysfunction in a rat model of heart failure. Chin Med J (Engl). 2012;125:807–14.

52.

• Hill MF, Patel AV, Murphy A, Smith HM, Galindo CL, Pentassuglia L, et al. Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1beta improves left ventricular function, gene and protein expression in rats after myocardial infarction. PLoS One. 2013;8:e55741. In this study, the effects of recombinant NRG were examined in a rat model of cardiac remodeling after myocardial infarction and were found to improve cardiac function in concert with suppressing/reversing a number of the protein and gene expression changes that occur in chronic heart failure.PubMedCentralPubMed

53.

Li B, Zheng Z, Wei Y, Wang M, Peng J, Kang T, et al. Therapeutic effects of neuregulin-1 in diabetic cardiomyopathy rats. Cardiovasc Diabetol. 2011;10:69.PubMedCentralPubMed

54.

Xiao J, Li B, Zheng Z, Wang M, Peng J, Li Y, et al. Therapeutic effects of neuregulin-1 gene transduction in rats with myocardial infarction. Coron Artery Dis. 2012;23:460–8.PubMed

55.

Gao R, Zhang J, Cheng L, Wu X, Dong W, Yang X, et al. A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol. 2010;55:1907–14.PubMed

56.

•• Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF, et al. Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail. 2011;13:83–92. In this clinical trial, the investigators define the hemodynamic response to recombinant NRG, showing its inodilator properties. Interestingly, the treatment was associated with improved myocardial function chronically that was most pronounced in the intermediate dose group.PubMed

57.

Moondra V, Sarma S, Buxton T, Safa R, Cote G, Storer T, et al. Serum neuregulin-1beta as a biomarker of cardiovascular fitness. Open Biomark J. 2009;2:1–5.PubMedCentralPubMed

58.

Ky B, Kimmel SE, Safa RN, Putt ME, Sweitzer NK, Fang JC, et al. Neuregulin-1 beta is associated with disease severity and adverse outcomes in chronic heart failure. Circulation. 2009;120:310–7.PubMedCentralPubMed

59.

Geisberg CA, Wang G, Safa RN, Smith HM, Anderson B, Peng XY, et al. Circulating neuregulin-1beta levels vary according to the angiographic severity of coronary artery disease and ischemia. Coron Artery Dis. 2011;22:577–82.PubMedCentralPubMed

60.

Geisberg CA, Abdallah WM, da Silva M, Silverstein C, Smith HM, Abramson V, et al. Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort. J Card Fail. 2013;19:10–5.PubMedCentralPubMed

61.

•• Zeng, Z., Gui, C., Nong, Q., Du, F., Zhu, L. Serum neuregulin-1beta levels are positively correlated with VEGF and Angiopoietin-1 levels in patients with diabetes and unstable angina pectoris. Int J Cardiol. 2013. On the basis of animal studies, one might predict that NRG is released by ischemia, even before myocardial injury. These authors measured serum NRG in patients with unstable angina and provide evidence to support this idea. The potential of NRG as a biomarker of ischemia is further supported by Ref. 50.

62.

Huertas-Vazquez A, Teodorescu C, Reinier K, Uy-Evanado A, Chugh H, Jerger K, et al. A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death. Heart Rhythm. 2013;10:994–8.PubMed

63.

Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71:877–92.PubMedCentralPubMed

64.

Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet. 2003;72:83–7.PubMedCentralPubMed

65.

Nicodemus KK, Luna A, Vakkalanka R, Goldberg T, Egan M, Straub RE, et al. Further evidence for association between ErbB4 and schizophrenia and influence on cognitive intermediate phenotypes in healthy controls. Mol Psychiatry. 2006;11:1062–5.PubMed

66.

Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, et al. Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:96–101.PubMed

67.

Ruschena D, Mullen PE, Burgess P, Cordner SM, Barry-Walsh J, Drummer OH, et al. Sudden death in psychiatric patients. Br J Psychiatry. 1998;172:331–6.PubMed

68.

Manu P, Kane JM, Correll CU. Sudden deaths in psychiatric patients. J Clin Psychiatry. 2011;72:936–41.PubMedCentralPubMed

69.

Carraway 3rd KL, Burden SJ. Neuregulins and their receptors. Curr Opin Neurobiol. 1995;5:606–12.PubMed

70.

Galindo, C., Truc-Tran, L., Ryzhov, S., Feoktistov, I., Sawyer, D.B. Neuregulin-1β Inhibits TGFβ-induced Cardiofibroblast to Myofibroblast Transition. Cardiovasc Res. 2013;113:Abstract 302.

71.

Brittain, E., Muldowney, J., Geisberg, C., Caggiano, A., Eisen, A., Anderson, S., et al. Evaluation of cardiac function in symptomatic heart failure patients in a single infusion, Phase 1, dose escalation study of glial growth factor 2. J Am Coll Cardiol. 2013;61.

72.

Lenihan, D.J., Anderson, S., Geisberg, C., Caggiano, A., Eisen, A., Brittain, E., et al. Safety and tolerability of glial growth factor 2 in patients with chronic heart failure: a phase I single dose escalation study. J Am Coll Cardiol. 2013;61.

73.

Odiete O, Konik EA, Sawyer DB, Hill MF. Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1beta/ErbB in response to myocardial infarction resulting in worsening heart failure. Cardiovasc Diabetol. 2013;12:52.PubMedCentralPubMed

74.

Miller TA, Icli B, Cote GM, Lebrasseur NK, Borkan SC, Pimentel DR, et al. Palmitate alters neuregulin signaling and biology in cardiac myocytes. Biochem Biophys Res Commun. 2009;379:32–7.PubMedCentralPubMed

75.

•• Jay SM, Murthy AC, Hawkins JF, Wortzel JR, Steinhauser ML, Alvarez LM, et al. An engineered bivalent neuregulin protects against Doxorubicin-induced cardiotoxicity with reduced proneoplastic potential. Circulation. 2013;128:152–61. These investigators engineered NRG to favor ErbB4 or ErbB3 homodimer formation, with the goal of removing ErbB2 activation during NRG stimulation. They provide intriguing evidence that such an approach can protect the heart and limit tumor growth.PubMed

76.

Force T, Wang Y. Mechanism-based engineering against anthracycline cardiotoxicity. Circulation. 2013;128:98–100.PubMed

77.

Jay SM, Kurtagic E, Alvarez LM, de Picciotto S, Sanchez E, Hawkins JF, et al. Engineered bivalent ligands to bias ErbB receptor-mediated signaling and phenotypes. J Biol Chem. 2011;286:27729–40.PubMed

78.

Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002;99:8880–5.PubMedCentralPubMed

79.

Garcia-Rivello H, Taranda J, Said M, Cabeza-Meckert P, Vila-Petroff M, Scaglione J, et al. Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am J Physiol Heart Circ Physiol. 2005;289:H1153–60.PubMed

80.

Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–65.PubMed

81.

Guma A, Martinez-Redondo V, Lopez-Soldado I, Canto C, Zorzano A. Emerging role of neuregulin as a modulator of muscle metabolism. Am J Physiol Endocrinol Metab. 2010;298:E742–50.PubMed

82.

Jie B, Zhang X, Wu X, Xin Y, Liu Y, Guo Y. Neuregulin-1 suppresses cardiomyocyte apoptosis by activating PI3K/Akt and inhibiting mitochondrial permeability transition pore. Mol Cell Biochem. 2012;370:35–43.PubMed

83.

Li J, Qiang O, Wang L. Effects of neuregulin on cardiac myocyte apoptosis and PI-3K signal transduction pathway in rapid pacing-induced heart failure in rhesus monkeys. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007;32:408–12.PubMed

84.

Rohrbach S, Muller-Werdan U, Werdan K, Koch S, Gellerich NF, Holtz J. Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. J Mol Cell Cardiol. 2005;38:485–93.PubMed

85.

Pentassuglia L, Timolati F, Seifriz F, Abudukadier K, Suter TM, Zuppinger C. Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp Cell Res. 2007;313:1588–601.PubMed

86.

Rentschler S, Zander J, Meyers K, France D, Levine R, Porter G, et al. Neuregulin-1 promotes formation of the murine cardiac conduction system. Proc Natl Acad Sci U S A. 2002;99:10464–9.PubMedCentralPubMed

87.

Ruhparwar A, Er F, Martin U, Radke K, Gruh I, Niehaus M, et al. Enrichment of cardiac pacemaker-like cells: neuregulin-1 and cyclic AMP increase I(f)-current density and connexin 40 mRNA levels in fetal cardiomyocytes. Med Biol Eng Comput. 2007;45:221–7.PubMed

88.

Ruhparwar A, Haverich A. Prospects for biological cardiac pacemaker systems. Pacing Clin Electrophysiol. 2003;26:2069–71.PubMed

89.

Matsukawa R, Hirooka Y, Ito K, Sunagawa K. Inhibition of neuregulin-1/ErbB signaling in the rostral ventrolateral medulla leads to hypertension through reduced nitric oxide synthesis. Am J Hypertens. 2013;26:51–7.PubMed

90.

Kalinowski A, Plowes NJ, Huang Q, Berdejo-Izquierdo C, Russell RR, Russell KS. Metalloproteinase-dependent cleavage of neuregulin and autocrine stimulation of vascular endothelial cells. FASEB J. 2010;24:2567–75.PubMed

91.

Hintsanen M, Elovainio M, Puttonen S, Kivimaki M, Raitakari OT, Lehtimaki T, et al. Neuregulin-1 genotype moderates the association between job strain and early atherosclerosis in young men. Ann Behav Med. 2007;33:148–55.PubMed

92.

• Safa RN, Peng XY, Pentassuglia L, Lim CC, Lamparter M, Silverstein C, et al. Neuregulin-1beta regulation of embryonic endothelial progenitor cell survival. Am J Physiol Heart Circ Physiol. 2011;300:H1311–9. This work demonstrates that a subpopulation of monocytes in the circulation that have been associated with cardiac repair respond to NRG with enhanced survival. Whether this set of cells is activated by NRG during cardiac injury/stress and mediates cardiac repair remains an open question.PubMed

93.

Lok J, Sardi SP, Guo S, Besancon E, Ha DM, Rosell A, et al. Neuregulin-1 signaling in brain endothelial cells. J Cereb Blood Flow Metab. 2009;29:39–43.PubMedCentralPubMed

94.

Li Q, Zhang R, Ge YL, Mei YW, Guo YL. Effects of neuregulin on expression of MMP-9 and NSE in brain of ischemia/reperfusion rat. J Mol Neurosci. 2009;38:207–15.PubMed

95.

Panutsopulos D, Arvanitis DL, Tsatsanis C, Papalambros E, Sigala F, Spandidos DA. Expression of heregulin in human coronary atherosclerotic lesions. J Vasc Res. 2005;42:463–74.PubMed

96.

Lok J, Zhao S, Leung W, Seo JH, Navaratna D, Wang X, et al. Neuregulin-1 effects on endothelial and blood-brain-barrier permeability after experimental injury. Transl Stroke Res. 2012;3:S119–24.PubMedCentralPubMed

97.

Marballi K, Quinones MP, Jimenez F, Escamilla MA, Raventos H, Soto-Bernardini MC, et al. In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation. J Mol Med (Berl). 2010;88:1133–41.

98.

Lemmens K, Doggen K, De Keulenaer GW. Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy. Am J Physiol Heart Circ Physiol. 2011;300:H931–42.PubMed

99.

Kim JS, Choi IG, Lee BC, Park JB, Kim JH, Jeong JH, et al. Neuregulin induces CTGF expression in hypertrophic scarring fibroblasts. Mol Cell Biochem. 2012;365:181–9.PubMed

100.

Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000;102:3060–7.PubMed

101.

Barisione C, Garibaldi S, Ghigliotti G, Fabbi P, Altieri P, Casale MC, et al. CD14CD16 monocyte subset levels in heart failure patients. Dis Markers. 2010;28:115–24.PubMedCentralPubMed

102.

Dixon DL, Griggs KM, Bersten AD, De Pasquale CG. Systemic inflammation and cell activation reflects morbidity in chronic heart failure. Cytokine. 2011;56:593–9.PubMed

103.

Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ Res. 2011;108:1133–45.PubMedCentralPubMed

104.

Leone F, Perissinotto E, Cavalloni G, Fonsato V, Bruno S, Surrenti N, et al. Expression of the c-ErbB-2/HER2 proto-oncogene in normal hematopoietic cells. J Leukoc Biol. 2003;74:593–601.PubMed

105.

Mograbi B, Rochet N, Imbert V, Bourget I, Bocciardi R, Emiliozzi C, et al. Human monocytes express amphiregulin and heregulin growth factors upon activation. Eur Cytokine Netw. 1997;8:73–81.PubMed

106.

Xu G, Watanabe T, Iso Y, Koba S, Sakai T, Nagashima M, et al. Preventive effects of heregulin-beta1 on macrophage foam cell formation and atherosclerosis. Circ Res. 2009;105:500–10.PubMed

107.

Okoshi K, Nakayama M, Yan X, Okoshi MP, Schuldt AJ, Marchionni MA, et al. Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation. 2004;110:713–7.PubMed

108.

Watanabe T, Sato K, Itoh F, Iso Y. Pathogenic involvement of heregulin-beta(1) in anti-atherogenesis. Regul Pept. 2012;175:11–4.PubMed

Title: Neuregulin as a Heart Failure Therapy and Mediator of Reverse Remodeling
Authors: Cristi L. Galindo
Sergey Ryzhov
Douglas B. Sawyer
Publication date: 01-03-2014
Publisher: Springer US
Published in: Current Heart Failure Reports / Issue 1/2014
Print ISSN: 1546-9530
Electronic ISSN: 1546-9549
DOI: https://doi.org/10.1007/s11897-013-0176-2

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2014

Exercise Intolerance in Chronic Heart Failure: The Role of Cortisol and the Catabolic State

Novel Blockers of the Renin-Angiotensin-Aldosterone System in Chronic Heart Failure

The Obesity Paradox in Chronic Heart Failure: What Does It Mean?

Abnormalities in Cardiopulmonary Exercise Testing Ventilatory Parameters in Heart Failure: Pathophysiology and Clinical Usefulness

Increased Mortality after an Acute Heart Failure Episode: New Pathophysiological Insights from the RELAX-AHF Study and Beyond

The Relationship Between Cardiac Resynchronization Therapy and Diastolic Function

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials