Our basic and translational research is focused on the mechanisms by which the heart maintains cardiac function and recovers after injury. Based upon this work we have helped to develop new ideas for treating heart failure.
Neuregulin and the Cardiovascular System
Neuregulin, a subset of the endothelial growth factor family of proteins known to play a role in vertebrate cardiac embryogensis, is re-activated in the adult heart during injury and changes in hemodynamic load. While in healthy subjects the level of neuregulin correlates with cardiopulmonary fitness, neuregulin levels correlate to cardiac stress in heart failure patients.
Neuregulin /ERBB Receptor Signaling
In response to stress, cardiac microvascular endothelial cells activate ERBB receptors in neighboring cells by proteolytically releasing NRG-1β. Depending on the cell type and context of release, NRG-1β activates one or more signaling cascades, including mitogen-activated protein kinase (MAPK), PI3K/AKT, p70/S6K, and Src/FAK pathways.
Microenvironmental Regulation of Cardiac Regeneration
Intramyocardial microenvironment determines the fate of human resident cardiac progenitor cells. We have recently identified a population of human progenitor cells that are characterized by the expression of both the CD105 cell marker and GATA-4 transcription factor.
Microenvironmental factors which induce activation of Wnt signaling results in generation and expansion of cardiac progenitors (Aisagbonhi et al, 2011).
Neuregulin-1β induces embryonic stem cell cardiomyogenesis via ErbB3/ErbB2 receptors (Hao et al, 2014). Cardiac stem/progenitor cells express ERBB2 and ERBB3 receptors and their stimulation with neuregulin-1 prevents differentiation towards myofibroblasts, reducing cardiac remodeling after heart injury (Galindo et al., 2014).
Our study identified A2B adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the heart. (Ryzhov et al, 2012).
Microenvironmental factors which mediate activation of Wnt-, ERBB- and AR- dependent signaling pathways promote generation, expansion and cardiomyogenic differentiation of resident CD105+CD31-CD45- cardiac progenitors, thus contributing to the rejuvenation of heart tissue in patients with heart failure.
Other ongoing areas of investigation:
- The role of retinoids in regulation of cardiac injury and failure
- Regulation of monocyte and fibroblast biology by neuregulin/ErbB signaling.
Shisler D, Austin TM, Delpire E, Sawyer DB, Pandey AK. Syndrome of severe pain associated with a continuous bumetanide infusion. International journal of cardiology. 2014; 177(2):e61-2. NIHMSID: NIHMS646295 PubMed [journal] PMID: 25304072, PMCID: PMC4283470
Galindo CL, Ryzhov S, Sawyer DB. Neuregulin as a heart failure therapy and mediator of reverse remodeling. Current heart failure reports. 2014; 11(1):40-9. NIHMSID: NIHMS540661 PubMed [journal] PMID: 24234399, PMCID: PMC3975684
Hao J, Galindo CL, Tran TL, Sawyer DB. Neuregulin-1β induces embryonic stem cell cardiomyogenesis via ErbB3/ErbB2 receptors. The Biochemical journal. 2014; 458(2):335-41. NIHMSID: NIHMS668922 PubMed [journal] PMID: 24364879, PMCID: PMC4654571
Bell SP, Adkisson DW, Ooi H, Sawyer DB, Lawson MA, et al. Impairment of subendocardial perfusion reserve and oxidative metabolism in nonischemic dilated cardiomyopathy. Journal of cardiac failure. 2013; 19(12):802-10. NIHMSID: NIHMS536518 PubMed [journal] PMID: 24331202, PMCID: PMC3945036
Pentassuglia L, Sawyer DB. ErbB/integrin signaling interactions in regulation of myocardial cell-cell and cell-matrix interactions. Biochimica et biophysica acta. 2013; 1833(4):909-16. PubMed [journal] PMID: 23261977
Odiete O, Konik EA, Sawyer DB, Hill MF. Type 1 diabetes mellitus abrogates compensatory augmentation of myocardial neuregulin-1β/ErbB in response to myocardial infarction resulting in worsening heart failure. Cardiovascular diabetology. 2013; 12:52. PubMed [journal] PMID: 23530877, PMCID: PMC3617023
Cote GM, Sawyer DB, Chabner BA. ERBB2 inhibition and heart failure. The New England journal of medicine. 2012; 367(22):2150-3. PubMed [journal] PMID: 23190227
Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circulation research. 2012; 111(10):1376-85. NIHMSID: NIHMS499083 PubMed [journal] PMID: 23104879, PMCID: PMC3752394