Douglas B. Sawyer, MD, PhD

Douglas B. Sawyer, MD, PhD 2017-09-07T11:12:45+00:00

Douglas B. Sawyer, MD, PhD

Co-Director, Myocardial Biology & Heart Failure Research Lab

Chief, Cardiovascular Services, Maine Medical Center

EDUCATION

BS: Cornell University
PhD: Cornell University Graduate School of Medical Science
MD: Cornell University Medical College

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.

Sawyer_Fig1

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.

Sawyer_Fig2.1

Sawyer_Fig2.2Microenvironmental 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.

Sawyer_Fig3Wnt signaling
Microenvironmental factors which induce activation of Wnt signaling results in generation and expansion of cardiac progenitors (Aisagbonhi et al, 2011).

NRG signaling
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).

Adenosine signaling
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.

Favreau_Amanda_TAmanda Lessard, PhD

Research Fellow
favrea2@mmc.org

Research Interests: learn more about Dr. Lessard’s research

Peterson_Sarah_TSarah Peterson, MD, PhD

Research Fellow
peters2@mmc.org

Research Interests: learn more about Dr. Peterson’s research

Robich_MichaelMichael Robich, MD, MSPH

Cardiothoracic Surgery
mrobich@mmc.org

 

Ryzhov_Sergey_TSergey Ryzhov, MD, PhD

Faculty Scientist I
sryzhov@mmc.org

Research Interests: learn more about Dr. Ryzhov’s research

Sawyer_Lab

Left side: Doug Sawyer, Sergey Rzyhov, Sarah Peterson Right side: Oleg Tikhomirov, Amanda Lessard, Ricky Rath

A complete list of publications can be found on My NCBI

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

 

The Science Sketch video below describes a collaborative project with the Neurocritical Care Department to determine if high Neuregulin levels correlate with improved survival after cardiac arrest.