Sergey Ryzhov, MD, PhD

Sergey Ryzhov, MD, PhD 2017-09-07T11:20:35+00:00

Sergey Ryzhov, MD, PhD

Co-Director, Myocardial Biology & Heart Failure Research Lab

Faculty Scientist I

EDUCATION

Undergraduate: Siberian State Medical University, Tomsk, Russia
PhD: Siberian State Medical University, Tomsk, Russia
Postdoctoral Training: Vanderbilt University, Nashville, TN

Interactions Between Immune and Cardiac Cells During Heart Recovery After Ischemic Heart Injury

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).

Ryzhov_Figure 1aFigure 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.

NRG-1/ERBB Signaling in Myeloid 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).

Ryzhov_Figure 2aFigure 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).

Ryzhov_Figure 3a

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).

A complete list of publications can be found on My NCBI

Ryzhov S., Solenkova N.V., Goldstein A.E., Lamparter M., Fleenor T., Young P.P., Greelish J.P., Byrne J.G, Vaughan D.E., Biaggioni I., Hatzopoulos A.K., Feoktistov I. Adenosine Receptor–Mediated Adhesion of Endothelial Progenitors to Cardiac Microvascular Endothelial Cells. Circ Res. 2008; 102(3): 356-363. PMCID: PMC2803108.

Novitsky S.V., Ryzhov S., Huang Y., Tikhomirov O.Y., Biaggioni I., Carbone D.P., Feoktistov I., Dikov M.M. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood. 2008; 112(5):1822-1831. PMCID: PMC2518889.

Ryzhov S., Novitsky S.V, Zaynagetdinov R., Goldstein A.E., Carbone D.P., Biaggioni I., Dikov M.M., Feoktistov I. Host A2B Adenosine Receptors Modulate Carcinoma Growth. Neoplasia. 2008; 10(9):987-995. PMCID: PMC2517644.

Aisagbonhi O., Rai M, Ryzhov S., Atria N., Feoktistov I., Hatzopoulos A.K. Experimental Myocardial Infarction Triggers Canonical Wnt Signaling and Endothelial-to-Mesenchymal Transition. Dis. Model Mech 2011; 4(4): 469-483 PMCID: PMC3124051.

Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I. Adenosinergic Regulation of the Expansion and Immunosuppressive Activity of CD11b+Gr1+ Cells. J Iimmunol. 2011; 187(11):6120-6129. PMCID: PMC3221925.

Ryzhov S., Goldstein A.E., Novitskiy S.V., Blackburn M.R., Biaggioni I., Feoktistov I. Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells. J Pharmacol Exp Ther. 2012; 341(3):764-774. PMCID: PMC3362889.

Ryzhov S, Zhang Q, Biaggioni I, Feoktistov I. Adenosine A2B Receptors on Cardiac Stem Cell Antigen (Sca)-1-Positive Stromal Cells Play a Protective Role in Myocardial Infarction. Am J Pathol. 2013; 183(3):665-672. PMCID: PMC3763763.

Ryzhov S, Biktasova A, Goldstein AE, Zhang Q, Biaggioni I, Dikov MM, Feoktistov I. Role of JunB in adenosine A2B receptor-mediated VEGF production. Mol Pharm 2014; 85(1):62-73. PMCID: PMC3868903.

Ryzhov S., Sung BH, Zhang Q, Weaver A, Gumina RJ, Biaggioni I, Feoktistov I. Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation. Purinergic Signal. 2014; 10(3):477-86. PMCID: PMC4152448.

Ryzhov S, Pickup P.W., Chytil A., Zhang Q., Owens P., Feoktistov I., Moses H.L., Novitskiy S.V. Role of TGFβ signaling in generation of CD39+CD73+ myeloid cells in tumors. J Immunol. 2014; 193(6):3155-164. PMCID:PMC4157098

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.