Posts Tagged: fibroblasts

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Joshua Mayourian, Delaine K. Ceholski, David M. Gonzalez, Timothy J. Cashman, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa

Endothelial–cardiomyocyte interplay through paracrine factors. Endothelial cell NO increases basal contractility via nitrosylation of L-type Ca2+ channel (LTCC) and ryanodine receptor (RyR2). NO attenuates β-adrenergic effects on cardiomyocyte excitation–contraction coupling via cGMP-dependent degradation of cAMP and protein kinase G (PKG)-mediated decrease of LTCC activity. PKG also phosphorylates troponin I, leading to myofilament calcium desensitization and thus increased lusitropy. Endothelin-1, which mainly acts through the endothelin A (ETA) receptor in ventricular cardiomyocytes, may increase calcium entry via protein kinase C (PKC)-mediated (1) increase of LTCC activity, (2) indirect activation of sodium–calcium exchanger (NCX) reverse mode by increasing Na+–H+ exchanger activity, and (3) direct activation of NCX reverse (shown) and forward (not shown) mode. Endothelin-1 alters myofilament Ca2+ sensitivity via protein kinase C/D (PKC/D) phosphorylation of troponin I and myosin-binding protein C. Finally, endothelin-1 may increase calcium-induced calcium release via inositol trisphosphate (IP3) activation of inositol trisphosphate receptor (IP3R), which sensitizes RyR2 on the sarcoplasmic reticulum (SR). Green and red arrows denote activation and inhibition, respectively. PLB indicates phospholamban; and SERCA, sarcoendoplasmic reticulum Ca2+-ATPase. [Powerpoint File]

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling

Joshua Mayourian, Delaine K. Ceholski, David M. Gonzalez, Timothy J. Cashman, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa

Human engineered cardiac tissue (hECT) contractility assay. A, hECTs are created, cultured, and tested in a custom bioreactor with integrated force-sensing end-posts; as the tissue beats, deflections of the end-posts are tracked. Output contractile metrics include, but are not limited to, developed force (DF), maximum rates of contraction and relaxation (+/− dF/dt, respectively), and beat rate. B, Confocal microscopy of hECTs labeled with cardiac troponin I (green) and DAPI (4’,6-diamidino-2-phenylindole; blue) displays cardiomyocytes with striated sarcomeres and regions of aligned myofibrils. Inset shows magnified view of registered sarcomeres. C, hECT labeled with sarcoendoplasmic reticulum Ca2+-ATPase 2 (red) and DAPI (blue) shows sarcoplasmic reticulum structures distributed throughout the tissue. Bar = 40 µm. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Selection of signaling pathways regulating myofibroblast activation and potential therapeutic targets for cardiac fibrosis. Numerous signaling pathways have been implicated in the activation of cardiac fibroblasts and the induction of pathological remodeling; targeting these signals is of intense scientific interest toward development of novel therapeutic strategies. Cardiac injury promotes the activation of receptors such as the β-adrenergic receptor (β-AR), activin receptor-like kinase 5 (ALK5), type 1 angiotensin II receptor (AT1R), endothelin receptor (ETR), transient receptor potential channel C6 (TRPC6), and integrins, which induces pathological signaling through numerous mediators, leading to the transcription of factors that regulate myofibroblast activation and fibrotic remodeling. Proposed antifibrotic therapeutic targets are marked with a red X. AC indicates adenylate cyclase; ERK1/2, extracellular regulated kinase 1/2; GRK2, G-protein–coupled receptor kinase 2; JNK, c-JUN N-terminal kinase; MEK1, mitogen-activated protein kinase kinase 1; MRTF, myocardin-related transcription factor; NFAT, nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; TAK1, TGF-β–activated kinase 1; and TGF-β, transforming growth factor β. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Characteristics and functions of activated cardiac myofibroblasts. Cardiac fibroblasts respond to pathological stress and environmental stimuli by transforming into myofibroblasts that (1) express elevated levels of various proinflammatory and profibrotic factors that directly contribute to inflammatory cell infiltration and fibroblast proliferation, (2) secrete high levels of matrix metalloproteinases and other extracellular matrix (ECM) degrading enzymes that facilitate fibroblast migration, and (3) contribute to the deposition of collagen and other ECM proteins, leading to scar formation. Although this adaptive fibrotic scar tissue maintains the structural integrity and pressure-generating capacity of the heart, myofibroblast persistence eventually leads to the development of adverse changes in ventricular structure and compliance, leading to the progression to heart failure. [Powerpoint File]

Cardiac Fibrosis: The Fibroblast Awakens

Cardiac Fibrosis: The Fibroblast Awakens

Joshua G. Travers, Fadia A. Kamal, Jeffrey Robbins, Katherine E. Yutzey, Burns C. Blaxall

Proposed sources of cardiac myofibroblasts. The source(s) of activated cardiac fibroblasts that accumulate in response to various pathological insults remains under active investigation. Mounting evidence suggests that activated myofibroblasts in the fibrotic heart derive from the proliferation and activation of resident fibroblasts, as these cells are remarkably sensitive to pathological insult and represent a feasible source of matrix-producing cells during cardiac fibrosis. Numerous additional precursors to the fibroblast population in the injured heart have been proposed; these include endothelial and epicardial cells, through epithelial–mesenchymal transition and endothelial–mesenchymal transition, respectively, hematopoietic bone marrow–derived cells, perivascular cells, and fibrocytes. Although supporting evidence exists for cellular sources of activated fibroblasts denoted by question marks, controversy remains about the functional contribution of these cell types to the cardiac myofibroblast population. Biomarkers with greater specificity will be required to fully characterize the pathophysiological relevance of these cell types in the cardiac fibrotic response, which will enable potential targeting for antifibrotic therapies. [Powerpoint File]

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

Takehiro Kamo, Hiroshi Akazawa, Issei Komuro

Intercellular communications between cardiomyocytes and nonmyocytes in the development of cardiac hypertrophy. Myocardial cell responses are regulated by intercellular communications between cardiomyocytes and nonmyocytes, such as fibroblasts, endothelial cells, and inflammatory cells. Cardiomyocytes secrete angiogenic factors to induce angiogenesis. An increase in capillary mass leads to increase in supply of nutrients and O2 necessary for hypertrophic growth. In addition, endothelial cells produce a variety of paracrine factors that exert prohypertrophic and antihypertrophic responses. During the development of cardiac hypertrophy, localized proliferation of both epicardium-derived and endocardium-derived fibroblast lineages contributes to extracellular matrix protein deposition and cardiac fibrosis. A wide variety of paracrine and autocrine factors mediate the intercellular communications between cardiac fibroblasts and cardiomyocytes in cardiac hypertrophy. During the development of cardiac hypertrophy, macrophages accumulate in ventricle both through localized proliferation and recruitment of circulating monocytes. Cardiac macrophages and mast cells are involved in induction of cardiac hypertrophy, although mechanistic link between T cells and the development of cardiac hypertrophy remains unclear. [Powerpoint File]

Direct Cardiac Reprogramming: Progress and Challenges in Basic Biology and Clinical Applications

Direct Cardiac Reprogramming: Progress and Challenges in Basic Biology and Clinical Applications

Taketaro Sadahiro, Shinya Yamanaka, Masaki Ieda

Future cardiac regenerative therapy. The lost myocardial tissue is replaced by fibrous tissue that mainly consists of cardiac fibroblasts and extracellular matrix. The cell transplantation–based approach using induced pluripotent stem cell (iPSC)–derived cardiomyocytes is shown (upper). Direct cardiac reprogramming approach may convert endogenous cardiac fibroblasts directly into cardiomyocytes by defined factors in situ (lower). [Powerpoint File]