Sergey Ryzhov, MD, PhD
Faculty Scientist III & Co-Director MBHFR Lab
Center for Molecular Medicine
Douglas B. Sawyer, MD, PhD
Faculty Scientist III & Co-Director MBHFR Lab
Center for Molecular Medicine
Myocardial Biology & Heart Failure Research Lab
Identifying the role of immune cells in ischemic tissues and its potential for enhancing blood supply to the heart and cardiac regeneration.
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.
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.
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.
Wnt 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:
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- The role of retinoids in regulation of cardiac injury and failure
- Regulation of monocyte and fibroblast biology by neuregulin/ErbB signaling
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Myocardial infarction (MI) is characterized by a marked cellular inflammatory response. CD45pos immune cells rapidly infiltrate injured myocardium, their numbers peaking at day 5 after MI when they become almost as abundant as all CD45neg non-myocyte cells (endothelial cell, fibroblasts, myofibroblasts, smooth muscle cells etc) combined (Fig. 1).
Myeloid cells are the majority of infiltrating cells during acute inflammatory and early reparative phases, and contribute to both pro-inflammatory and anti-inflammatory reactions. Our laboratory is primarily interested in studying the role of myeloid cells in the activation of cardiac progenitor cells and microvascular endothelial cells. We are currently characterizing the role of immune cells in the development of specific phenotype of cardiac mesenchymal stem-like cells using in vitro co-culture of conditionally immortalized cardiac Sca-1posCD31neg cells and different subpopulations of myeloid cells, including Ly6Gpos neutrophils, Ly6Chigh and Ly6Clow/neg monocytes, F4/80pos macrophages and monocyte-derived dendritic cells, generated from bone marrow derived lineage negative hematopoietic progenitor cells (HPC). We also investigating the molecular mechanisms involved in effects of adenosine differentiated dendritic cells (ADDC) on proliferation and morphogenic activity of microvascular endothelial cells.
Neuregulins (NRGs) belong to the epidermal growth factor (EGF) superfamily of transmembrane growth factors and included four members: NRG-1, NRG-2, NRG-3, and NRG-4. Among all neuregulins, NRG-1 has been intensively studied due to its essential role in cardiac development and in regulation of the adult cardiovascular system adaptation to physiological and pathological stress. NRGs signal through neuregulin receptors which include ERBB2, ERBB3 and ERBB4. NRG-1 binds to ERBB3 or ERBB4, and induces homo- and- heterodimer formation with each other (ERBB3/4 heterodimer, ERBB4/4 homodimer) or with ERBB2 (ERBB3/2 or ERBB4/2 heterodimers). ERBB2 has no ligand binding ability; its involvement in NRG-1 signaling is dependent upon heterodimerization with ERBB3 or ERBB4. Dimerization followed by tyrosine phosphorylation results in subsequent activation of downstream intracellular mediators of signaling including PI3K/AKT, Src/FAK, extracellular-regulated kinase (ERK1/2), nitric oxide synthase and cardiac myosin light chain kinase (cMLCK) (Fig. 2).
Figure 2
The protective effect of NRG-1 has been shown in a variety of pathophysiological cardiovascular conditions, including ischemic and anthracycline heart injury, and heart failure. The current paradigm holds non-immune cells as a primary target for protective effects of NRG-1. Our preliminary data, however, indicate that human monocytes express ERBB2 and ERBB3 receptors and NRG-1 signaling pathway in myeloid cells contributes to resolution of inflammation by promoting the functional shift from cytokine-secreting “pro-inflammatory” toward phagocytic “pro-resolution” phenotype (Fig. 3).
Figure 3
To study this phenomenon, we have developed a novel mouse model with cell type-specific deletion of Erbb3 gene expression in myeloid cells (ERBB3MyeKO).