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Penelope A. Boyden - One of the best experts on this subject based on the ideXlab platform.

  • microtubular remodeling and decreased expression of nav1 5 with enhanced ehd4 in cells from the Infarcted Heart
    Life Sciences, 2018
    Co-Authors: Wen Dun, Peter Danilo, Peter J. Mohler, Penelope A. Boyden
    Abstract:

    Abstract Cardiac Na+ channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the Infarcted canine Heart. Recent studies show that Nav1.5 cytoskeletal- and endosomal-based membrane trafficking and function are linked to tubulin, microtubular (MT) networks, and Eps15 homology domain containing proteins like EHD4. Aim Our objective is to understand the relation of tubulin and EHD4 to Nav1.5 channel protein remodeling observed in border zone cells (IZs) when arrhythmias are known to occur; that is, 3-h, 48-h and 5-day post coronary occlusion. Materials methods findings Our voltage clamp and immunostaining data show that INa density is decreased in the epicardial border zone cells of the 48 h Infarcted Heart (IZ48h). Immunostaining studies reveal that in post MI cells the cell surface staining of Nav1.5 was reduced and Nav1.5 distribution changed. However, intense co-staining of Nav1.5 and tubulin occurs in core planes and the perinuclear areas in post MI cells. At the same time, there were marked changes in the subcellular location of the EHD4 protein. EHD4 is co-localized with tubulin protein in discrete intracellular “highway” structures. Significance The distribution and expression of the three proteins are altered dynamically in post MI cells. In sum, our work illustrates the spatiotemporal complexity of remodeling mechanisms in the post-infarct myocyte. It will be important in future experiments to further explore direct links between MT, EHD proteins, and cell proteins involved in forward trafficking.

  • Microtubular remodeling and decreased expression of Nav1.5 with enhanced EHD4 in cells from the Infarcted Heart
    Life sciences, 2018
    Co-Authors: Wen Dun, Peter Danilo, Peter J. Mohler, Penelope A. Boyden
    Abstract:

    Cardiac Na+ channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the Infarcted canine Heart. Recent studies show that Nav1.5 cytoskeletal- and endosomal-based membrane trafficking and function are linked to tubulin, microtubular (MT) networks, and Eps15 homology domain containing proteins like EHD4. Our objective is to understand the relation of tubulin and EHD4 to Nav1.5 channel protein remodeling observed in border zone cells (IZs) when arrhythmias are known to occur; that is, 3-h, 48-h and 5-day post coronary occlusion. Our voltage clamp and immunostaining data show that INa density is decreased in the epicardial border zone cells of the 48 h Infarcted Heart (IZ48h). Immunostaining studies reveal that in post MI cells the cell surface staining of Nav1.5 was reduced and Nav1.5 distribution changed. However, intense co-staining of Nav1.5 and tubulin occurs in core planes and the perinuclear areas in post MI cells. At the same time, there were marked changes in the subcellular location of the EHD4 protein. EHD4 is co-localized with tubulin protein in discrete intracellular "highway" structures. The distribution and expression of the three proteins are altered dynamically in post MI cells. In sum, our work illustrates the spatiotemporal complexity of remodeling mechanisms in the post-infarct myocyte. It will be important in future experiments to further explore direct links between MT, EHD proteins, and cell proteins involved in forward trafficking. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  • dynamic remodeling of k and ca2 currents in cells that survived in the epicardial border zone of canine healed Infarcted Heart
    American Journal of Physiology-heart and Circulatory Physiology, 2004
    Co-Authors: Wen Dun, Shigeo Baba, Takuya Yagi, Penelope A. Boyden
    Abstract:

    Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 Infarcted Heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs ap...

  • Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed Infarcted Heart
    American journal of physiology. Heart and circulatory physiology, 2004
    Co-Authors: Wen Dun, Shigeo Baba, Takuya Yagi, Penelope A. Boyden
    Abstract:

    Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 Infarcted Heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca2+ and K+ currents in cells isolated from the 14-day (IZ14d) and 2-mo (IZ2m) EBZ and compared them with those occurring in cells from the same Hearts but remote (Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca2+ and K+ currents in cells from the different groups. Ca2+ current densities remain reduced in cells of the 14-day and 2-mo Infarcted Heart and the kinetic changes previously identified in the 5-day Heart begin to, but do not recover to, cells from nonInfarcted epicardium (NZ) values. Importantly, I(Ca,L) in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca2+ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in beta-adrenergic responsiveness of I(Ca,L) exists between EBZ and remote cells of the 14-day Hearts, but this regional heterogeneity is gone in the healed Infarcted Heart. In IZ14d, the transient outward K+ current (Ito) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, Ito and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast Ito but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering I(Ca,L) of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I(Ca,L) "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.

  • electrical remodeling of the epicardial border zone in the canine Infarcted Heart a computational analysis
    American Journal of Physiology-heart and Circulatory Physiology, 2003
    Co-Authors: Candido Cabo, Penelope A. Boyden
    Abstract:

    The density and kinetics of several ionic currents of cells isolated from the epicardial border zone of the Infarcted Heart (IZs) are markedly different from cells from the nonInfarcted canine epic...

Dinender K. Singla - One of the best experts on this subject based on the ideXlab platform.

  • regulation of pten akt pathway enhances cardiomyogenesis and attenuates adverse left ventricular remodeling following thymosin β4 overexpressing embryonic stem cell transplantation in the Infarcted Heart
    PLOS ONE, 2013
    Co-Authors: Binbin Yan, Pawan K. Singal, Reetu D Singla, Latifa S Abdelli, Dinender K. Singla
    Abstract:

    Thymosin β4 (Tβ4), a small G-actin sequestering peptide, mediates cell proliferation, migration, and angiogenesis. Whether embryonic stem (ES) cells, overexpressing Tβ4, readily differentiate into cardiac myocytes in vitro and in vivo and enhance cardioprotection following transplantation post myocardial infarction (MI) remains unknown. Accordingly, we established stable mouse ES cell lines, RFP-ESCs and Tβ4-ESCs, expressing RFP and an RFP-Tβ4 fusion protein, respectively. In vitro, the number of spontaneously beating embryoid bodies (EBs) was significantly increased in Tβ4-ESCs at day 9, 12 and 15, compared with RFP-ESCs. Enhanced expression of cardiac transcriptional factors GATA-4, Mef2c and Txb6 in Tβ4-EBs, as confirmed with real time-PCR analysis, was accompanied by the increased number of EB areas stained positive for sarcomeric α-actin in Tβ4-EBs, compared with the RFP control, suggesting a significant increase in functional cardiac myocytes. Furthermore, we transplanted Tβ4-ESCs into the Infarcted mouse Heart and performed morphological and functional analysis 2 weeks after MI. There was a significant increase in newly formed cardiac myocytes associated with the Notch pathway, a decrease in apoptotic nuclei mediated by an increase in Akt and a decrease in levels of PTEN. Cardiac fibrosis was significantly reduced, and left ventricular function was significantly augmented in the Tβ4-ESC transplanted group, compared with controls. It is concluded that genetically modified Tβ4-ESCs, potentiates their ability to turn into cardiac myocytes in vitro as well as in vivo. Moreover, we also demonstrate that there was a significant decrease in both cardiac apoptosis and fibrosis, thus improving cardiac function in the Infarcted Heart.

  • MicroRNA-1 transfected embryonic stem cells enhance cardiac myocyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the Infarcted Heart.
    American journal of physiology. Heart and circulatory physiology, 2011
    Co-Authors: Carley Glass, Dinender K. Singla
    Abstract:

    microRNAs (miRs) have emerged as critical modulators of various physiological processes including stem cell differentiation. Indeed, miR-1 has been reported to play an integral role in the regulation of cardiac muscle progenitor cell differentiation. However, whether overexpression of miR-1 in embryonic stem (ES) cells (miR-1-ES cells) will enhance cardiac myocyte differentiation following transplantation into the Infarcted myocardium is unknown. In the present study, myocardial infarction (MI) was produced in C57BL/6 mice by left anterior descending artery ligation. miR-1-ES cells, ES cells, or culture medium (control) was transplanted into the border zone of the Infarcted Heart, and 2 wk post-MI, cardiac myocyte differentiation, adverse ventricular remodeling, and cardiac function were assessed. We provide evidence demonstrating enhanced cardiac myocyte commitment of transplanted miR-1-ES cells in the mouse Infarcted Heart as compared with ES cells. Assessment of apoptosis revealed that overexpression of miR-1 in transplanted ES cells protected host myocardium from MI-induced apoptosis through activation of p-AKT and inhibition of caspase-3, phosphatase and tensin homolog, and superoxide production. A significant reduction in interstitial and vascular fibrosis was quantified in miR-1-ES cell and ES cell transplanted groups compared with control MI. However, no statistical significance between miR-1-ES cell and ES cell groups was observed. Finally, mice receiving miR-1-ES cell transplantation post-MI had significantly improved Heart function compared with respective controls (P < 0.05). Our data suggest miR-1 drives cardiac myocyte differentiation from transplanted ES cells and inhibits apoptosis post-MI, ultimately giving rise to enhanced cardiac repair, regeneration, and function.

  • Stem cells in the diabetic Infarcted Heart
    Heart Failure Reviews, 2010
    Co-Authors: Carley E. Glass, Pawan K. Singal, Dinender K. Singla
    Abstract:

    Diabetes mellitus is one of the leading causes of death, and the majority of these deaths are associated with cardiovascular diseases . Development and progression of myocardial infarction leading to Heart failure is much more complex and multifactorial in diabetics compared with non-diabetics. Despite significant advances in pharmacological interventions and surgical techniques, the disease progression leading to diabetic end-stage Heart failure remains very high. Recently, cell therapy has gained much attention as an alternative approach to treat various Heart diseases. However, transplanted stem cell studies in diabetic animal models are very limited. In this review, we discuss the pathogenesis of the diabetic Infarcted Heart and the potential of stem cell therapy to repair and regenerate.

  • stem cells in the Infarcted Heart
    Journal of Cardiovascular Translational Research, 2010
    Co-Authors: Dinender K. Singla
    Abstract:

    Stem cell transplantation is currently generating a significant interest for use in the future treatment of cardiovascular diseases. Stem cell populations are rapidly increasing, and we are still in the search of optimal cell types to use in clinical trials as bone marrow stem cells did not show significant improvement in cardiac function following transplantation. Experimental stem cell studies raised the question on the true differentiation of tissue-specific cell types following transplantation. In fact, recent studies suggest that improved cardiac function is associated with inhibition of apoptosis and fibrosis provided by factors released from stem cells following transplantation. In this review, we will discuss the effects of transplanted stem cells on engraftment and differentiation as well as factors released from stem cells on apoptosis and cardiac remodeling.

Nikolaos G. Frangogiannis - One of the best experts on this subject based on the ideXlab platform.

  • Abstract MP123: The Fate and Role of Pericytes in Repair and Remodeling of the Infarcted Heart
    Circulation Research, 2020
    Co-Authors: Linda Alex, Nikolaos G. Frangogiannis
    Abstract:

    Repair of the Infarcted Heart is dependent on inflammation-driven activation of myofibroblasts (MFs) and subsequent formation of a scar. Though pericytes have been implicated in injury-associated fibroblast activation in several organs, their potential role in cardiac repair and fibrosis has not been studied. We hypothesized that myocardial infarction (MI) may induce pericyte activation, contributing to repair through pericyte to MF conversion, secretion of fibrogenic mediators, or regulation of angiogenesis. In order to test the hypothesis, we generated pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ). In normal myocardium, NG2 labeled peri-endothelial mural cells that coexpressed PDGFRβ, whereas PDGFRα identified interstitial cells with fibroblast characteristics. Pericytes and fibroblasts had distinct transcriptomic profiles: NG2+/PDGFRα- pericytes expressed αSMA and low amounts of extracellular matrix (ECM) genes, whereas PDGFRα+/NG2- fibroblasts synthesized collagens. Pericyte rarefaction was noted in the necrotic core 3 days after non-reperfused MI. 3-7 days post MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of ColIα2 (7.2±1.0-fold) and ColIIIα1 (8.9±1.14-fold), when compared to NG2+/PDGFRα- cells from normal Hearts. NG2+ cells had high mRNA levels of integrins α1, αV, β1, and β5, and of MMP14, reflecting an activated migratory phenotype. To examine whether expression of ECM genes by infarct pericytes is due to fibroblast conversion, we did lineage tracing studies using NG2CreER TM ;Rosa tdTomato mice bred with the PDGFRα GFP line for reliable fibroblast identification. 7 days post MI, 5.7%±1.04 of PDGFRα+ fibroblasts were derived from NG2+ cells. Also, αSMA staining showed that 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. The majority of mural cells wrapping neovessels were derived from NG2+ cells, suggesting a role for resident pericytes in infarct angiogenesis. In conclusion, upon MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.

  • macrophage smad3 protects the Infarcted Heart stimulating phagocytosis and regulating inflammation
    Circulation Research, 2019
    Co-Authors: Bijun Chen, Shuaibo Huang, Anis Hanna, Adipong Brickshawana, Jonathan M. Graff, Nikolaos G. Frangogiannis
    Abstract:

    Rationale: TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad ...

  • Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation.
    Circulation research, 2019
    Co-Authors: Bijun Chen, Shuaibo Huang, Anis Hanna, Adipong Brickshawana, Jonathan M. Graff, Nikolaos G. Frangogiannis
    Abstract:

    TGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the Infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling. To investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function. TGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell-specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in Infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments. We demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the Infarcted Heart from adverse remodeling.

  • Pericytes in the Infarcted Heart
    Vascular Biology, 2019
    Co-Authors: Linda Alex, Nikolaos G. Frangogiannis
    Abstract:

    The adult mammalian Heart lacks regenerative capacity and heals through activation of an inflammatory cascade that leads to the formation of a collagen-based scar. Although scar formation is important to preserve the structural integrity of the ventricle, unrestrained inflammation and excessive fibrosis have been implicated in the pathogenesis of adverse post-infarction remodeling and Heart failure. Interstitial cells play a crucial role in the regulation of cardiac repair. Although recent studies have explored the role of fibroblasts and immune cells, the cardiac pericytes have been largely ignored by investigators interested in myocardial biology. This review manuscript discusses the role of pericytes in the regulation of inflammation, fibrosis and angiogenesis following myocardial infarction. During the inflammatory phase of infarct healing, pericytes may regulate microvascular permeability and may play an important role in leukocyte trafficking. Moreover, pericyte activation through Toll-like receptor-mediated pathways may stimulate cytokine and chemokine synthesis. During the proliferative phase, pericytes may be involved in angiogenesis and fibrosis. To what extent pericyte to fibroblast conversion and pericyte-mediated growth factor synthesis contribute to the myocardial fibrotic response remains unknown. During the maturation phase of infarct healing, coating of infarct neovessels with pericytes plays an important role in scar stabilization. Implementation of therapeutic approaches targeting pericytes in the Infarcted and remodeling Heart remains challenging, due to the lack of systematic characterization of myocardial pericytes, their phenotypic heterogeneity and the limited knowledge on their functional role.

  • Distinct roles of myofibroblast-specific Smad2 and Smad3 signaling in repair and remodeling of the Infarcted Heart.
    Journal of molecular and cellular cardiology, 2019
    Co-Authors: Shuaibo Huang, Linda Alex, Bijun Chen, Claudio Humeres, Arti V. Shinde, Simon J. Conway, Nikolaos G. Frangogiannis
    Abstract:

    TGF-βs regulate fibroblast responses, by activating Smad2 or Smad3 signaling, or via Smad-independent pathways. We have previously demonstrated that myofibroblast-specific Smad3 is critically implicated in repair of the Infarcted Heart. However, the role of fibroblast Smad2 in myocardial infarction remains unknown. This study investigates the role of myofibroblast-specific Smad2 signaling in myocardial infarction, and explores the mechanisms responsible for the distinct effects of Smad2 and Smad3. In a mouse model of non-reperfused myocardial infarction, Smad2 activation in infarct myofibroblasts peaked 7 days after coronary occlusion. In vitro, TGF-β1, -β2 and -β3, but not angiotensin 2 and bone morphogenetic proteins-2, -4 and -7, activated fibroblast Smad2. Myofibroblast-specific Smad2 and Smad3 knockout mice (FS2KO, FS3KO) and corresponding control littermates underwent non-reperfused infarction. In contrast to the increase in rupture rates and adverse remodeling in FS3KO mice, FS2KO animals had mortality comparable to Smad2 fl/fl controls, and exhibited a modest but transient improvement in dysfunction after 7 days of coronary occlusion. At the 28 day timepoint, FS2KO and Smad2 fl/fl mice had comparable adverse remodeling. Although both FS3KO and FS2KO animals had increased myofibroblast density in the infarct, only FS3KO mice exhibited impaired scar organization, associated with perturbed alignment of infarct myofibroblasts. In vitro, Smad3 but not Smad2 knockdown downmodulated fibroblast α2 and α5 integrin expression. Moreover, Smad3 knockdown reduced expression of the GTPase RhoA, whereas Smad2 knockdown markedly increased fibroblast RhoA levels. Smad3-dependent integrin expression may be important for fibroblast activation, whereas RhoA may transduce planar cell polarity pathway signals, essential for fibroblast alignment. Myofibroblast-specific Smad3, but not Smad2 is required for formation of aligned myofibroblast arrays in the infarct. The distinct in vivo effects of myofibroblast Smad2 and Smad3 may involve Smad3-dependent integrin synthesis, and contrasting effects of Smad2 and Smad3 on RhoA expression.

Yao Sun - One of the best experts on this subject based on the ideXlab platform.

  • differential expression of vascular endothelial growth factor isoforms and receptor subtypes in the Infarcted Heart
    International Journal of Cardiology, 2013
    Co-Authors: Tieqiang Zhao, Wenyuan Zhao, Yuanjian Chen, Li Liu, Robert A Ahokas, Yao Sun
    Abstract:

    Abstract Aims The vascular endothelial growth factor (VEGF) family contains four major isoforms and three receptor subtypes. The expressions of each VEGF isoform and receptor subtype in cardiac repair/remodeling after myocardial infarction (MI) remain uncertain and are investigated in the current study. Methods and results Temporal and spatial expressions of VEGF isoforms and VEGFR subtypes were examined in the Infarcted rat Heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all VEGF isoforms. Following MI, VEGF-A was only increased in the border zone at day 1 and was significantly decreased in the Infarcted Heart during the 42 day observation period afterwards. VEGF-B was significantly suppressed in the Infarcted Heart. VEGF-C and VEGF-D were markedly increased in the Infarcted Heart in both early and late stages of MI. VEGFR-1 and 2 were significantly decreased in the Infarcted Heart, while VEGFR-3 was significantly increased, which was primarily expressed in blood vessels and myofibroblasts (myoFb). Conclusions VEGF isoforms and VEGFR subtypes are differentially expressed in the Infarcted Heart. Increased VEGF-A in the very early stage of MI suggests the potential role in initiating the cardiac angiogenic response. Suppressed cardiac VEGF-B postMI suggests that it may not be critical to cardiac repair. The presence of enhanced VEGF‐C and VEGF-D along with its receptor, VEGFR-3, in various cell types of the Infarcted Heart suggest that these isoforms may regulate multiple responses during cardiac repair/remodeling.

  • Differential expression of vascular endothelial growth factor isoforms and receptor subtypes in the Infarcted Heart.
    International journal of cardiology, 2012
    Co-Authors: Tieqiang Zhao, Wenyuan Zhao, Yuanjian Chen, Li Liu, Robert A Ahokas, Yao Sun
    Abstract:

    The vascular endothelial growth factor (VEGF) family contains four major isoforms and three receptor subtypes. The expressions of each VEGF isoform and receptor subtype in cardiac repair/remodeling after myocardial infarction (MI) remain uncertain and are investigated in the current study. Temporal and spatial expressions of VEGF isoforms and VEGFR subtypes were examined in the Infarcted rat Heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all VEGF isoforms. Following MI, VEGF-A was only increased in the border zone at day 1 and was significantly decreased in the Infarcted Heart during the 42 day observation period afterwards. VEGF-B was significantly suppressed in the Infarcted Heart. VEGF-C and VEGF-D were markedly increased in the Infarcted Heart in both early and late stages of MI. VEGFR-1 and 2 were significantly decreased in the Infarcted Heart, while VEGFR-3 was significantly increased, which was primarily expressed in blood vessels and myofibroblasts (myoFb). VEGF isoforms and VEGFR subtypes are differentially expressed in the Infarcted Heart. Increased VEGF-A in the very early stage of MI suggests the potential role in initiating the cardiac angiogenic response. Suppressed cardiac VEGF-B postMI suggests that it may not be critical to cardiac repair. The presence of enhanced VEGF-C and VEGF-D along with its receptor, VEGFR-3, in various cell types of the Infarcted Heart suggest that these isoforms may regulate multiple responses during cardiac repair/remodeling. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  • Fibrosis: a living tissue and the Infarcted Heart.
    Journal of the American College of Cardiology, 2008
    Co-Authors: Karl T. Weber, Yao Sun, Javier Díez
    Abstract:

    Heart failure has reached epidemic proportions among the elderly, in whom it is most often attributable to an ischemic cardiomyopathy (ICM) with previous myocardial infarction(s) (MIs). The Infarcted Heart is a “house divided” ([1][1]), its myocardium disrupted by the loss of necrotic

  • angiotensin ii transforming growth factor β1and repair in the Infarcted Heart
    Journal of Molecular and Cellular Cardiology, 1998
    Co-Authors: Yao Sun, John Q Zhang, Jiakun Zhang, Felix J A Ramires
    Abstract:

    Tissue repair following myocardial infarction (MI) eventuates in fibrous tissue formation at the site of myocyte necrosis. Following a large transmural MI, fibrosis appears remote to the infarct site. This is associated with extensive tissue remodeling that adversely affects ventricular diastolic function. Substances involved in promoting fibrous tissue formation at MI and remote sites are under investigation. Angiotensin II (AngII), generated at sites of repair, has been implicated. However, its regulatory role on fibrous tissue formation remains uncertain. In the present study we sought to determine whether AngII is correlated to transforming growth factor beta 1 (TGF-beta1) expression, a regulator of fibrous tissue formation, at these sites of tissue repair. We studied: (1) localization and expression of angiotensin converting enzyme (ACE), AngII receptors, TGF-beta1 mRNA and its receptors in the Infarcted rat Heart; and (2) effect of AngII on TGF-beta1 synthesis by chronic blockade of AT1 receptors began at the time of surgery by losartan in rats with MI. Hearts were studied at 4 weeks post-MI. We found: (1) low-density ACE, AngII and TGF-beta1 receptor binding and low mRNA for type I collagen and TGF-beta1 in the normal Heart; (2) fibrosis at sites of MI and remote to it, including endocardium and fibrosis of intraventricular septum, interstitial fibrosis of non-Infarcted myocardium and fibrosis of visceral pericardium; (3) markedly increased (P<0.01) and colocalized ACE, AngII and TGF-beta1 receptor binding, type I collagen and TGF-beta1 mRNA at MI and remote sites of repair; (4) increased TGF-beta1 concentration (P<0. 01) at these sites; and (5) attenuated TGF-beta1 and type I collagen gene expression (P<0.01) at these sites in rats receiving losartan. These observations suggest locally generated AngII via ATi receptor binding is correlated to TGF-beta1 expression and synthesis at sites of repair and remote sites in the Infarcted rat Heart. The mechanism responsible for the role of AngII in TGF-beta1 remains to be elucidated.

Penelopeboyden - One of the best experts on this subject based on the ideXlab platform.

  • Transient Outward Currents in Subendocardial Purkinje Myocytes Surviving in the Infarcted Heart
    Circulation, 1995
    Co-Authors: Cynthiajeck, Judithpinto, Penelopeboyden
    Abstract:

    Background Altered electrical activity of subendocardial Purkinje fibers contributes to arrhythmias in the 48-hour Infarcted canine Heart. Changes in the transmembrane action potentials of these fibers include marked action potential prolongation. The ionic basis for these changes is unknown. Methods and Results We used whole-cell voltage-clamp techniques to study 4-aminopyridine (4-AP)–sensitive voltage-dependent transient outward currents (Ito1) in Purkinje myocytes isolated from LV subendocardial (n=14) and free-running (n=15) bundles of the normal canine Heart. Ito1 in these two groups of control cells (normal-zone Purkinje cells [NZPCS]) did not differ. NZPCS Ito1 was then compared with Ito1 of Purkinje myocytes dispersed from subendocardium of Infarcted Hearts 48 hours after total coronary artery occlusion (IZPC48, n=14). Ito1 amplitude and current density were significantly reduced (P