Neuregulins are growth factors that act in a paracrine manner in diverse tissues through the erbB family of receptor tyrosine kinases. A body of work including that from our own laboratory suggests that neuregulin-1 (NRG-1) plays a role in endothelial cell-myocyte crosstalk, and recent clinical data suggests that this system may play a role in the alterations in cardiac structure and function that occur in heart failure. We have used in vitro studies of cardiac myocytes and endothelial cells in primary culture to understand the role of the neuregulin-erbB system in the myocardium. We have found that a recombinant NRG-1 can both activate and inactivate growth pathways in isolated cardiac cells. Moreover we have found that NRG-1 can activate anti-apoptotic signaling as well as increase the expression of cytoprotective antioxidant enzymes in isolated ventricular mycoytes. We have further found that cardiac microvascular endothelial cells express NRG-1alpha, and increase NRG-1alpha expression in response to several stimuli implicated in the pathogenesis of heart failure. These observations have lead to the overall hypothesis that NRG-1-erbB signaling in the adult myocardium maintains myocardial structure and function through the regulation of growth and survival signaling pathways, and is upregulated in response to remodeling stimuli resulting in a dampening of myocardial remodeling responses. We will approach this hypothesis in 5 specific aims, using in vitro studies of cardiac myocytes and endothelial cells, and in vivo models of myocardial remodeling. Collectively this work will help to determine how NRG-1-erbB signaling exacerbates or modulates myocardial remodeling in the setting of myocardial dysfunction, and may ultimately lead to novel therapeutic approaches to interrupt adverse myocardial remodeling leading to the progression of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068144-01
Application #
6368752
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Reinlib, Leslie
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$281,750
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Rath, Rutwik; Lee, Jung Bok; Tran, Truc-Linh et al. (2016) Biomimetic microstructure morphology in electrospun fiber mats is critical for maintaining healthy cardiomyocyte phenotype. Cell Mol Bioeng 9:107-115
Lenneman, Carrie G; Abdallah, Wissam M; Smith, Holly M et al. (2014) Sympathetic nervous system alterations with HER2+ antagonism: an early marker of cardiac dysfunction with breast cancer treatment? Ecancermedicalscience 8:446
Hill, Michael F; Patel, Amish V; Murphy, Abigail et al. (2013) Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1? improves left ventricular function, gene and protein expression in rats after myocardial infarction. PLoS One 8:e55741
Geisberg, Carrie A; Abdallah, Wissam M; da Silva, Monica et al. (2013) Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort. J Card Fail 19:10-5
Odiete, Oghenerukevwe; Konik, Ewa A; Sawyer, Douglas B et al. (2013) Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1?/ErbB in response to myocardial infarction resulting in worsening heart failure. Cardiovasc Diabetol 12:52
Lenneman, Andrew J; Wang, Li; Wigger, Mark et al. (2013) Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. Am J Cardiol 111:609-12
Pentassuglia, Laura; Sawyer, Douglas B (2013) ErbB/integrin signaling interactions in regulation of myocardial cell-cell and cell-matrix interactions. Biochim Biophys Acta 1833:909-16
Odiete, Oghenerukevwe; Hill, Michael F; Sawyer, Douglas B (2012) Neuregulin in cardiovascular development and disease. Circ Res 111:1376-85
Chen, Billy; Zhong, Lin; Roush, Sarah F et al. (2012) Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy. PLoS One 7:e35743
Cote, Gregory M; Sawyer, Douglas B; Chabner, Bruce A (2012) ERBB2 inhibition and heart failure. N Engl J Med 367:2150-3

Showing the most recent 10 out of 37 publications