Abstract 92: Platelet Derived Growth Factor Receptor Alpha Signaling is Required for Cardiac Fibroblast Survival and Proliferation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Malina J Ivey ◽  
Michelle D Tallquist
Keyword(s):  
Preliminary Data ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Fibroblast Proliferation ◽  
Artery Ligation ◽  
Developing Heart ◽  
Factor Receptor Alpha

Cardiac fibrosis contributes significantly to heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis, but identification of signaling pathways required for fibroblast function would provide some potential targets. PDGFRα is a receptor tyrosine kinase that is required for fibroblast formation in the developing heart, and preliminary data indicates that it is also required for maintenance of resident fibroblasts and expansion of activated fibroblasts after injury. Preliminary experiments demonstrate that loss of PDGFRα expression in adult cardiac fibroblasts results in 50% reduction in the number of the resident fibroblasts by 4 days after gene deletion. This was further validated using an independent fibroblast marker, collagen1a1GFP. Based on the low basal level of fibroblast proliferation, we hypothesize that PDGFRα signaling is essential for fibroblast survival and that fibroblasts undergo rapid turnover in the absence of PDGFRα signaling. Future studies will determine the exact mechanism of this loss. We have also begun to elucidate which PDGFRα downstream signals promote fibroblast maintenance. Using a PDGFRα-dependent-PI3K-deficient mouse model, preliminary data indicates that PDGFRα-dependent PI3K signaling is essential for cell survival. We are also investigating the role of PDGFRα signaling after myocardial infarction. Using recently described genetic tools to follow fibroblasts after injury, we have determined that fibroblasts reach their peak of proliferation within a week after permanent left anterior descending artery ligation. This injury-induced proliferation is reduced by 50% after deletion of PDGFRα. Therefore, we have demonstrated that PDGFRα has a role in fibroblast maintenance in the healthy heart, as well as a role in fibroblast proliferation after injury. Our studies will continue to illuminate additional roles for PDGFRα in the fibroblast, as well as the implications of fibroblast loss on other cell types and overall heart function.

Abstract 250: Elucidating the Role of Platelet Derived Growth Factor Receptor Alpha Signaling in Cardiac Fibroblasts

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Malina J Ivey ◽  
Michelle Tallquist
Keyword(s):  
Preliminary Data ◽  
Time Course ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Cardiac Fibroblast ◽  
Proliferating Cells ◽  
Time Course Experiment

Cardiac fibrosis is a major component of heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis directly. This major hurdle can be overcome by targeting the resident fibroblast. Preliminary data demonstrates that loss of PDGFRα expression in the adult cardiac fibroblast lineage results in loss of over half of resident fibroblasts. A time course experiment revealed that in as little as 4 days after PDGFRα gene deletion fibroblast loss can observed. Based on the basal level of fibroblast proliferation (0.8%+/-0.9, i.e. 4 of 398 cells), we hypothesize that PDGFRα signaling is essential for fibroblast maintenance and that fibroblasts undergo rapid turnover. We have begun to elucidate which downstream signals of PDGFRα are involved the different roles of the fibroblast. Using a PDGFRα-dependent-PI3K-deficient mouse model, preliminary data indicates that PDGFRα-dependent PI3K signaling is involved in this cell survival response. Future studies will investigate cardiac fibroblast maintenance signals by determining which cell types secrete PDGF ligands. We will also investigate the role of PDGFRα signaling after myocardial infarction. Our lab has genetic tools that enable us to follow fibroblasts after injury, and we have determined both the number of proliferating fibroblasts at different time points, as well as the fraction of fibroblasts that make up the total population of proliferating cells after LAD ligation. Our preliminary data in control hearts shows that fibroblasts reach their peak of proliferation within a week after infarction, although they remain one of the most proliferative cell types as long as three weeks after induction. Our studies will illuminate the role of the fibroblast in tissue homeostasis and after infarction and identify how these cells contribute to overall cardiovascular function and delineate the fine balance between the essential and detrimental functions of the fibroblast.

scholarly journals Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kenichi Kimura ◽  
Karina Ramirez ◽  
Tram Anh Vu Nguyen ◽  
Yoshito Yamashiro ◽  
Aiko Sada ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Vascular Diseases ◽  
Cell Types ◽  
Lineage Tracing ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Factor Receptor Alpha ◽  
Adventitial Cells

AbstractThe maladaptive remodeling of vessel walls with neointima formation is a common feature of proliferative vascular diseases. It has been proposed that neointima formation is caused by the dedifferentiation of mature smooth muscle cells (SMCs). Recent evidence suggests that adventitial cells also participate in neointima formation; however, their cellular dynamics are not fully understood. In this study, we utilized a lineage tracing model of platelet-derived growth factor receptor alpha (PDGFRa) cells and examined cellular behavior during homeostasis and injury response. PDGFRa marked adventitial cells that were largely positive for Sca1 and a portion of medial SMCs, and both cell types were maintained for 2 years. Upon carotid artery ligation, PDGFRa-positive (+) cells were slowly recruited to the neointima and exhibited an immature SMC phenotype. In contrast, in a more severe wire denudation injury, PDGFRa+ cells were recruited to the neointima within 14 days and fully differentiated into SMCs. Under pressure overload induced by transverse aortic constriction, PDGFRa+ cells developed marked adventitial fibrosis. Taken together, our observations suggest that PDGFRa+ cells serve as a reservoir of adventitial cells and a subset of medial SMCs and underscore their context-dependent response to vascular injuries.

scholarly journals Cryo-Electron Microscopy Structure and Interactions of the Human Cytomegalovirus gHgLgO Trimer with Platelet-Derived Growth Factor Receptor Alpha

mBio ◽  
2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Jing Liu ◽  
Adam Vanarsdall ◽  
Dong-Hua Chen ◽  
Andrea Chin ◽  
David Johnson ◽  
...  
Keyword(s):  
Birth Defects ◽  
Adult Population ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
The Body ◽  
Platelet Derived Growth Factor ◽  
Cryo Electron Microscopy ◽  
Factor Receptor Alpha ◽  
Complex Protein ◽  
Different Cell Types

HCMV is a herpesvirus that infects a large percentage of the adult population and causes significant levels of disease in immunocompromised individuals and birth defects in the developing fetus. The virus encodes a complex protein machinery that coordinates infection of different cell types in the body, including a trimer formed of gH, gL, and gO subunits.

Abstract 13837: Adrenergic Receptors β2 and β3 Transduce Differential Signals in Cardiac Fibroblasts

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kota Tonegawa ◽  
Hiroyuki Nakayama ◽  
Hiromi Igarashi ◽  
Sachi Matsunami ◽  
Nao Hayamizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cell Types ◽  
Neonatal Rat ◽  
Rt Pcr ◽  
Β Blocker ◽  
Selective Agonists ◽  
Selective Blocker ◽  
Camkii Activation

Background: Cardiac fibroblasts (CFs) are the most prevalent cell types in heart and play important roles in cardiac remodeling. While the roles of β-adrenergic receptor (βAR) signaling in cardiomyocytes (CMs) are well characterized, those in CFs remain to be elusive due to lack of convenient method to assess those signaling. There are three subtypes of, βAR β1, β2, β3 and β2AR is reported to be expressed in CFs by which enhances cell proliferation and production of inflammatory cytokines. Clinical efficacy of non-selective β blocker carvedilol for heart failure (HF) surpasses that of β1 selective blocker metoprolol, suggesting critical roles of β2 and β3AR in the pathogenesis of HF. Objective: To elucidate the signaling downstream βARs in CFs in heart. Methods and Results: Caveolae is an important microdomain for signal transduction, such as βAR, present in CMs or CFs. To elucidate βAR signaling of caveolae in CFs, we generated a fusion protein composed of phospholamban (PLN) and caveolin3 (Cav3) representing PKA activation as phosphorylation at S16 of PLN and CaMKII as that at T17 in caveolae. Thus, activation of PKA or CaMKII is detectable by anti-phospho-S16 or T17 antibody, respectively. In neonatal rat CFs (NRCFs) infected PLN-Cav3 adenovirus, stimulation by isoproterenol (ISO) led to enhanced phosphorylation of both S16 and T17, suggesting PKA and CaMKII activation in caveolae of CFs. RT-PCR analyses showed β2AR and β3AR were present in NRCFs. Stimulation with β2AR selective agonists activated both PKA and CaMKII, while β3AR elicited solely PKA activation, analyzed by using β3AR selective agonist/antagonist. In addition, in order to examine the significance of βAR stimulation for heart failure, we administered ISO continuously for two weeks in β2ARKO mice. As a result, fibrosis was suppressed in β2ARKO mice compared with wild-type mice (0.35% vs 2.37%, p<0.05) suggesting critical roles of β2AR in development of cardiac fibrosis caused by βAR stimulation in mice. Conclusions: Both β2 and β3AR are expressed in NRCFs and transduce distinct signaling and β2AR selective stimulation elicit development of cardiac fibrosis via activation of CaMKII signaling. Thus, selective βAR regulation could be potential novel anti-fibrotic therapeutics in HF.

Novel role for cardiac myocyte-derived β-2 microglobulin in mediating cardiac fibrosis

2018 ◽  
Vol 132 (19) ◽  
pp. 2117-2120
Author(s):  
Michael J. Boyer ◽  
Satoru Eguchi
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Cardiac Fibroblasts ◽  
Significant Risk ◽  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Significant Risk Factor ◽  
Cardiac Complications

Hypertension is a significant risk factor for the development of cardiovascular ailments, including ischemic heart disease and diastolic dysfunction. In a recent issue of Clinical Science, Li et al. [Clin. Sci. (2018) 132, 1855–1874] report that β-2 microglobulin (β2M) is a novel secreted soluble factor released by cardiac myocytes during pressure overload that promotes profibrotic gene expression in cardiac fibroblasts both in vitro and in vivo. Their study further identifies elevated β2M levels as a possible biomarker for hypertensive patients with cardiac complications. The authors propose a mechanism that mechanically stretched cardiomyocytes release soluble β2M which, through paracrine communication with cardiac fibroblasts, transactivates epidermal growth factor receptor (EGFR) to initiate acute signal transduction and up-regulate profibrotic genes, thereby promoting fibrosis. Here, we will discuss the background, significance of the study, alternative mechanisms, and future directions.

scholarly journals Pathogen at the Gates: Human Cytomegalovirus Entry and Cell Tropism

2018 ◽  
Author(s):  
Christopher C. Nguyen ◽  
Jeremy P. Kamil
Keyword(s):  
Human Cytomegalovirus ◽  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Stable Complex ◽  
Cell Tropism ◽  
The Past ◽  
Factor Receptor Alpha ◽  
Glycoprotein H ◽  
Substantial Progress

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that the virus infects. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRa) were identified as receptors, respectively, for the trimeric and pentameric glycoprotein H/glycoprotein L (gH/gL) complexes that in large part govern HCMV cell tropism, while CD90 and CD147 were also found to play roles during entry. X-ray crystal structures for the proximal viral fusogen, glycoprotein B (gB), and for the pentameric gH/gL complex (pentamer) have been solved. A novel virion gH complex consisting of gH bound to UL116 instead of gL was described, and findings supporting the existence of a stable complex between gH/gL and gB were reported. Additional work indicates that the pentamer promotes a mode of cell-associated spread that resists antibody neutralization, as opposed to the trimeric gH/gL complex (trimer), which appears to be broadly required for the infectivity of cell-free virions. Finally, viral factors such as UL148 and US16 were identified that can influence the incorporation of the alternative gH/gL complexes into virions. We will review these advances and their implications for understanding HCMV entry and cell tropism.

Abstract 380: Resident Cardiac Fibroblasts Give Rise to Periostin+ Myofibroblasts Which are the Primary Mediators of Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Onur Kanisicak ◽  
Hadi Khalil ◽  
Jason Karch ◽  
Matthew Brody ◽  
Suh-Chin Lin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cardiac Fibrosis ◽  
Bone Marrow Cells ◽  
Cardiac Fibroblasts ◽  
Critical Role ◽  
Cell Types ◽  
Lineage Tracing ◽  
Matricellular Protein ◽  
Mesenchymal Transition ◽  
Activated Fibroblasts

Resident cardiac fibroblasts (CFs) are potential therapeutic targets in treating or preventing heart failure since they play a critical role in cardiac remodeling and fibrosis after injury or with prolonged stress stimulation. Heterogeneity among activated fibroblasts within the heart has been noted by a number of previous studies in the literature. In addition to resident CFs, many cell types such as endothelial, perivascular and bone marrow cells have been suggested to go through a mesenchymal transition and acquire a myofibroblast-like phenotype during disease conditions. Hence, the cellular origin of the activated myofibroblast within the heart remains uncertain, in part because of a lack in reliable genetic strategies to define cellular lineage. Recent studies suggest that epicardial precursor cells expressing transcription factor 21 (Tcf21) give rise to resident CFs in the adult heart. In addition, the secreted matricellular protein periostin (Postn), appears to be expressed only within activated fibroblasts (myofibroblasts) within the heart. Here we used Tcf21-MerCreMer (Tcf21MCM) knockin mice and Postn-MerCreMer (PostnMCM) knock-in (KI) mice to lineage trace resident CFs and myofibroblasts with injury stimulation. To account for other potential cellular lineages giving rise to fibroblasts in the heart we also performed lineage tracing with the mouse genetic models including LysM-Cre (macrophage), ckit-Cre (bone marrow), Tie2CreERT2 (endothelial) and Myh11-CreERT2 (smooth muscle) in conjunction ROSA26 (R26) locus based loxP inactivated reporter alleles. Results of this study indicate that the Tcf21+ resident CFs are the predominant source for the activated periostin+ MFs which are the key mediators of extracellular matrix (ECM) production and ECM stability in heart whereas the contribution of other lineages to MFs are minimal. Additionally, we have performed single cell RNA sequencing on TCF21+ and Postn+ isolated CFs pre and post myocardial injury in order to define the fibroblast lineage itself at greater molecular depth.

Abstract 108: Exercise Promotes a Cardioprotective Gene Program in Resident Cardiac Fibroblasts

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Janet K Lighthouse ◽  
Ryan Burke ◽  
Lissette S Velasquez ◽  
Ronald A Dirkx ◽  
Christine S Moravec ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Transcriptional Profiling ◽  
Transcriptional Response ◽  
Mapk Signaling ◽  
Transcriptional Responses ◽  
Human Heart Failure ◽  
Antioxidant Genes ◽  
Cellular Source

Exercise and disease both induce hypertrophic cardiac growth, but only disease results in fibrosis and compromised heart function. Transcriptional profiling of resident cardiac fibroblasts (CFs), the primary cellular source of fibrosis, was used to define the gene expression programs (GEP) underlying this divergent functional outcome. Bioinformatic analyses revealed distinct transcriptional responses to exercise and disease, including induction of Rho- and SRF-dependent remodeling genes in disease and NRF2-dependent antioxidant genes in exercise. The expression of a number of antioxidant genes, including metallothioneins (Mt1 and Mt2), are specifically maintained in CFs after exercise and lost in disease. Mice lacking Mt1/2 show signs of cardiac dysfunction after exercise, including cardiac fibrosis, vascular rarefaction, and reduced heart function. Importantly, Mt levels are also reduced in human heart failure (HF) patients, suggesting a potentially conserved cardioprotective role in humans. Non-canonical TGF-β1-mediated p38-MAPK signaling has previously been implicated in HF, therefore we tested the role of p38 signaling in Mt regulation. Pharmacological inhibition of p38 in human HF fibroblasts restores Mt1 and Mt2 expression and blunts the pathological fibroblast phenotype. Taken together, our study defines the transcriptional response of CFs to exercise and disease and reveals a cardioprotective mechanism that is lost in disease.

scholarly journals Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin

2021 ◽  
Author(s):  
Ryan M Burke ◽  
Ronald A Dirkx, Jr. ◽  
Pearl Quijada ◽  
Janet K Lighthouse ◽  
Amy Mohan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Models ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Functional Decline ◽  
Cell Types ◽  
Ischemic Heart ◽  
Interventional Treatment ◽  
Heart Failure Patients

Rationale: Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts, called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. Objective: We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient derived cardiac fibroblasts and pre-clinical mouse models of ischemic and non-ischemic heart failure. Methods and Results: Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In pre-clinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and non-ischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates pre-established pathological cardiac remodeling secondary to hypertension, and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. Conclusions: These data establish salinomycin as an anti-fibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients.

scholarly journals Fenofibrate Induced Cardiac Fibrosis in Mice Deficient in the Protein Quality Control Regulator, CHIP

2018 ◽  
Author(s):  
Saranya Ravi ◽  
Traci L. Parry ◽  
Monte S. Willis ◽  
Pamela Lockyer ◽  
Cam Patterson ◽  
...  
Keyword(s):  
Energy Demand ◽  
Cardiac Fibrosis ◽  
Protein Quality ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Cell Types ◽  
Cardiac Metabolism ◽  
Peroxisome Proliferator ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor

We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long- and medium-chain fatty acid metabolites in wild-type hearts, a response that was attenuated in mice that lack expression of CHIP (CHIP-/-). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism, pathways that are regulated in part by the nuclear receptor PPAR&alpha; (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP-/- mice with the PPAR&alpha; agonist, fenofibrate. Surprisingly, treating CHIP-/- mice with fenofibrate for five weeks under non-pressure overload conditions resulted in a loss of skeletal muscle mass and a marked increase in cardiac fibrosis, accompanied by a decrease in cardiac function. Isolated CHIP-/- cardiac fibroblasts treated with fenofibrate did not increase synthesis of collagen or TGF&beta;, suggesting that the fibrosis observed in CHIP-/- hearts likely depends on signaling from other cell types or circulating factors. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism.

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