Abstract 204: Inhibition of Histone Deacetylase Activity Represses Matrix Metalloproteinase-9 Induction Through Regulation of Macrophage Polarization

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Denise M Kimbrough ◽  
Santhosh K Mani ◽  
Christine B Kern ◽  
Francis G Spinale ◽  
Rupak Mukherjee ◽  
...  
Keyword(s):  
Trichostatin A ◽  
Macrophage Polarization ◽  
Specific Inhibitor ◽  
Immunohistochemical Analysis ◽  
Left Ventricular ◽  
Class I ◽  
Lv Function ◽  
M2 Macrophage ◽  
Hdac Inhibition ◽  
Ecm Remodeling

Post myocardial infarction (MI) the extracellular matrix (ECM) undergoes massive remodeling in order to prevent dilation of the infarct area and maintain cardiac output. Integral players in this remodeling are matrix metalloproteinases (MMP). Post-MI macrophages are a significant source of MMP production and have been shown to have temporal expression of the two phenotypes (M1 and M2). Differential expressions of macrophage phenotypes correlate with the different phases of ECM remodeling, ECM composition and MMP expression. Increased expression of MMP-9 is associated with deleterious effects to the ECM and left ventricular (LV) dilation following MI. MMPs major mechanism of expression regulation is transcription. Histone deacetylases (HDAC) are a class of enzymes that can greatly affect transcriptional regulation of genes during pathological conditions. Therefore, we hypothesize that HDAC inhibition controls the post-MI expression of MMP-9 by mediating macrophage polarization to improve LV function. The post-MI change in LV end-diastolic volume is significantly lower with treatment of the class I and IIb HDAC inhibitor trichostatin A (TSA) and ejection fraction is improved in mice. Immunohistochemical analysis and zymography revealed that MMP-9 expression at 7 days post-MI is attributable to infiltrating macrophages. Immunoblotting shows that TSA inhibits control levels and lipopolysacharide (LPS) stimulated upregulation of MMP-9 in cultured macrophages, while the class I specific inhibitor, PD106, only inhibits control. The HDAC 6 inhibitor, Tubastatin A (Tub A), partially inhibits LPS stimulated upregulation of MMP-9, but surprisingly appears to potentiate control levels of MMP-9. Immunofluorescence revealed that direct HDAC inhibition with PD106, Tub A, and TSA leads to M1 to M2 macrophage polarization and maintenance of anti-inflammatory, M2, phenotype even with LPS stimulation in culture. From these data we conclude that macrophage secretion of MMPs is an essential component in the promotion of adverse ECM remodeling post-MI. HDAC inhibition can attenuate this remodeling possibly through macrophage polarization, but HDAC inhibition mediated M2 polarization may not be sufficient to suppress MMP-9 expression.

Abstract 223: Histone Deacetylase Inhibition Mediated Macrophage Polarization Suppresses Matrix Metalloproteinase-9 Upregulation Post Myocardial Infarction

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Denise M Kimbrough ◽  
Santhosh K Mani ◽  
Chistine B Kern ◽  
Harinath Kasiganesan ◽  
Donald R Menick
Keyword(s):  
Myocardial Infarction ◽  
Matrix Metalloproteinase ◽  
Macrophage Polarization ◽  
Matrix Metalloproteinase 9 ◽  
Class I ◽  
M2 Macrophage ◽  
Hdac Inhibition ◽  
Ecm Remodeling ◽  
M2 Macrophage Polarization ◽  
Metalloproteinase 9

Background: Following a myocardial infarction (MI) the extracellular matrix (ECM) undergoes massive remodeling to prevent rupture and maintain cardiac output. Large increases in matrix metalloproteinase-9 (MMP-9) are associated with adverse ECM remodeling. We found that treatment with an HDAC inhibitor repressed post-MI upregulation of MMP-9. Significant sources of MMP-9 in the post-MI LV are M1 macrophages. Both phenotypes (M1 and M2) can contribute to MMP expression, but this is dependant on the phase of ECM remodeling. We hypothesize that HDAC inhibition regulates the post-MI expression of MMP-9 by mediating the M1 to M2 macrophage polarization. Methods: CD1 and MMP-9 β-gal reporter mice were induced with MI by LAD ligation then administered HDAC inhibitors: trichostatin A (TSA; class I and IIb), PD106 (class I), or Tubastatin A (HDAC 6) until termination at 5 or 7 days post-MI. Heart function evaluated by echocardiogram and cells or tissue by immunohistochemistry and immunoblotting. Results: The post-MI change in LV end-diastolic volume (49±9%) is significantly lower and ejection fraction (-44±8%) is improved with treatment of TSA vs. control (69±12%; -59±6%) respectively [n=28]. Immunohistochemical analysis revealed that infiltrating macrophages express MMP-9 at 5 and 7 days post-MI. HDAC inhibition decreases this expression and did so without reducing presence of macrophages within infarct. Immunoblotting shows that expression of all class I HDACs are increased following MI; however, in cultured macrophages only HDAC2 and HDAC3 are increased. TSA and PD106, inhibit control levels and lipopolysacharide (LPS) stimulated upregulation of MMP-9 in cultured RAW264.7 and bone marrow derived macrophages. Immunofluorescence revealed that treatment with PD106, Tub A, and TSA leads to M1 to M2 morphology specific polarization and maintenance of anti-inflammatory, M2, phenotype even with LPS stimulation in culture. However, only PD106 and TSA reduced MMP-9 expression in cultured macrophages. Conclusions: Macrophage mediated secretion of MMP-9 contributes to adverse ECM remodeling and loss of LV function post-MI. Class I HDAC inhibition promotes both M2 macrophage polarization and attenuates adverse remodeling by reducing MMP-9 expression.

Abstract 222: Inhibition Of Class I But Not Class IIb Lysine Deacetylases Is Responsible For Cardioprotection From Ischemia-Reperfusion.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sverre E Aune ◽  
Santhosh K Mani ◽  
Donald R Menick
Keyword(s):  
Contractile Function ◽  
Trichostatin A ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Specific Inhibition ◽  
Isolated Hearts ◽  
Class Iib

Background: While dual inhibition of class I/IIb KDACs protects the mammalian heart from ischemia-reperfusion (IR) injury, class-specific effects have not been examined. Hypothesis: We hypothesized that specific inhibition of class I KDACs would preserve left ventricular (LV) function following IR in isolated hearts. Methods: Male Sprague-Dawley rats (n=4 per group) were injected with vehicle, the class I KDAC inhibitor entinostat, the class IIb inhibitor tubastatin A, or the class I/IIb inhibitor trichostatin A (TSA). After 18 h, hearts were isolated and perfused in Langendorff mode. A saline-filled balloon was placed in the LV to monitor contractile function. Following IR (30/120 min), LV free wall tissue was assayed for activation of pro-survival proteins. Group results are reported vs vehicle as mean±SE. Results: There were no differences between groups in LV function before ischemia. At the end of reperfusion, rate pressure product (mm hg/min) was improved with entinostat (27392±3474, p<0.001) and TSA (22980±3226, p<0.05) vs vehicle (11,352±1977), as were +dP/dt max and -dP/dt max . Most notably, entinostat alone blunted the rise in end diastolic pressure (mm Hg) during reperfusion (18.6±1.4 vs. 45.3±4.1, p<0.001), and completely prevented diastolic contracture (mm Hg) in reperfusion for up to one hour (12.4±2.0 vs pre-ischemia=8.7±1.7, p=0.21). Contractile function was not significantly preserved in hearts treated with tubastatin A. Entinostat reduced phosphorylation at the eNOS inhibitory site, and increased phosphorylation at the eNOS activation site, and Src activation was dramatically reduced. TSA increased activation of Src, p38, and ERK 1/2, and increased phosphorylation of eNOS at both the activation (Ser1177) and inhibition site (Thr495). Tubastatin A reduced activation of p38, ERK 1/2, and eNOS, but not Src. Conclusions: Inhibition of class I KDACs was most effective at preserving contractile function following IR in isolated hearts, notably through prevention of LV contracture during reperfusion. Class I KDAC inhibition may preserve LV function by differentially modulating Src and eNOS activities. These results suggest that the protective effects of KDAC inhibitors in IR can be ascribed to specific inhibition of class I KDACs.

scholarly journals Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

2015 ◽  
Vol 308 (11) ◽  
pp. H1391-H1401 ◽  
Author(s):  
Santhosh K. Mani ◽  
Christine B. Kern ◽  
Denise Kimbrough ◽  
Benjamin Addy ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Left Ventricular ◽  
Class I ◽  
Matrix Metalloproteinase 2 ◽  
Lv Function ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lv Remodeling

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

Abstract 405: Inhibition of Class I Histone Deacetylases at Reperfusion Attenuates Ischemia-reperfusion Injury and Modifies Mitochondrial Acetylation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Mitochondrial Enzymes ◽  
Reperfusion Phase

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage occurs as a consequence of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Here, we tested the hypothesis that MS-275 treatment at reperfusion reduces LV tissue damage and improves post-ischemic LV contractile function. To do this, hearts from male Sprague-Dawley rats were isolated and perfused ex vivo on a Langendorff perfusion apparatus. A saline-filled balloon was inserted into the left ventricle of the heart to monitor ventricular pressure development throughout the experiment. Hearts were subjected to 30 minutes of ischemia, followed by 60 minutes of reperfusion. MS-275 was administered during the entire reperfusion phase, and resultant functional data were compared to untreated hearts. There was no difference in any metric of pre-ischemic contractile function between groups. 10nM MS-275 administered at reperfusion significantly improved multiple measures of LV function, including dP/dtmax, -dP/dtmax, developed pressure and rate pressure product. We also observed a significant reduction in infarct area of treated hearts compared to control, as measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Unexpectedly, mass spectrometry analysis revealed significant changes in acetylation state of multiple mitochondrial enzymes. Administration of MS-275 during the reperfusion phase of IR is sufficient to partially rescue LV function from reperfusion-induced damage. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion.

scholarly journals Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

2014 ◽  
Vol 307 (5) ◽  
pp. H752-H761 ◽  
Author(s):  
William M. Yarbrough ◽  
Catalin Baicu ◽  
Rupak Mukherjee ◽  
An Van Laer ◽  
William T. Rivers ◽  
...  
Keyword(s):  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Matrix Remodeling ◽  
Protective Effects ◽  
Ecm Remodeling ◽  
Hypertrophic Response ◽  
Lv Mass ◽  
And Function

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

scholarly journals Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

2018 ◽  
Vol 49 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Patrick Lugenbiel ◽  
Katharina Govorov ◽  
Ann-Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Action Potential Duration ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class I ◽  
K Channel ◽  
Hdac Inhibition ◽  
Atrial Cardiomyocytes ◽  
Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

scholarly journals Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

2011 ◽  
Vol 111 (6) ◽  
pp. 1778-1788 ◽  
Author(s):  
Kirk R. Hutchinson ◽  
Anuradha Guggilam ◽  
Mary J. Cismowski ◽  
Maarten L. Galantowicz ◽  
Thomas A. West ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Dysfunction ◽  
Volume Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Stroke Work ◽  
Important Indicator ◽  
Ecm Remodeling ◽  
Functional Changes ◽  
Custom Made

Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/β-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.

scholarly journals Targeted deletion of NF-κB p50 diminishes the cardioprotection of histone deacetylase inhibition

2010 ◽  
Vol 298 (6) ◽  
pp. H2154-H2163 ◽  
Author(s):  
L. X. Zhang ◽  
Y. Zhao ◽  
G. Cheng ◽  
T. L. Guo ◽  
Y. E. Chin ◽  
...  
Keyword(s):  
Trichostatin A ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Luciferase Assay ◽  
Short Interfering Rna ◽  
Hdac Inhibition ◽  
Wild Type ◽  
Simulated Ischemia ◽  
H9c2 Cardiomyoblasts ◽  
Interfering Rna

We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of NF-κB p50 would eliminate the protective effects of HDAC inhibition. Wild-type and NF-κB p50-deficient mice were treated with trichostatin A (TSA; 0.1 mg/kg ip), a potent inhibitor of HDACs. Twenty-four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia and 30 min of reperfusion. Inhibition of HDACs by TSA in wild-type mice produced marked improvements in left ventricular end-diastolic pressure, left ventricular rate pressure product, and the reduction of infarct size compared with non-TSA-treated group. TSA-induced cardioprotection in wild-type animals was absent with genetic deletion of NF-κB p50 subunit. Notably, Western blot displayed a significant increase in nuclear NF-κB p50 and the immunoprecipitation demonstrated a remarkable acetylation of NF-κB p50 at lysine residues following HDAC inhibition. EMSA exhibited a subsequent increase in NF-κB DNA binding activity. Luciferase assay demonstrated an activation of NF-κB by HDAC inhibition. The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased in cell viability in simulated ischemia. The resistance of H9c2 cardiomyoblasts to simulated ischemia by HDAC inhibition was eliminated by genetic knockdown of NF-κB p50 with transfection of NF-κB p50 short interfering RNA but not scrambled short interfering RNA. These results suggest that NF-κB p50 acetylation and activation play a pivotal role in HDAC inhibition-induced cardioprotection.

P6297Genetic mutation of galectin-3 altered the temporal evolution of macrophage polarization and healing affecting the post myocardial infarct remodeling in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G Gonzalez ◽  
P D Cassaglia ◽  
F Penas ◽  
N L Martinez ◽  
C Bettazza ◽  
...  
Keyword(s):  
Wound Healing ◽  
Mrna Expression ◽  
Temporal Evolution ◽  
Macrophage Polarization ◽  
Weight Ratio ◽  
Lv Function ◽  
M2 Macrophage ◽  
Infarct Zone ◽  
Tnf Α ◽  
Galectin 3

Abstract Background Myocardial infarction (MI) is a dynamic process that leads to ventricular remodeling (VR) and largely to heart failure (HF). Previous studies established that Galectin-3 (Gal-3) is highly increased in the infarct zone from the beginning of MI and also that it is a prognostic marker of HF. Purpose We aimed to study the effects of genetic deletion of Gal-3 on macrophage (MΦ) infiltration, cytokines expression, fibrosis and MMP-2 activity as well as VR and function after MI in mice. Methods Male C57BL/6J and Gal-3 KO mice were subjected to permanent coronary ligature or sham. At 1 week post-MI LV function and VR were studied by echocardiography. We also studied in the infarct zone: 1) F4/80+ MΦ infiltration by flow cytometry; 2) M2 macrophage polarization by detection of mannose receptor (MR) and chitinase-3-like protein-3 (YM1) phenotype markers by rt-qPCR; 3) mRNA expression of TNF-α, IL-6, IL-10 and TGF-β; 4) MMP-2 activity by zymography and 5) fibrosis by histology. Results Results are expressed as X±SEM; *p<0.05 C57 MI vs Gal-3 KO MI. After 1 week post-MI, the pulmonary congestion assessed by the lung weight/body weight ratio (mg/g) was 9±0.4, 8±0.5 and 9±0.4 in C57 sham, Gal-3 KO sham and C57 MI, respectively, nevertheless it was severely increased to 15±1.2* in infarcted Gal-3 KO mice. MΦ infiltration, cytokine expression and MMP-2 activity in the infarct zone are shown in the table. Table 1 Groups F4/80+ MR YM1 TNF-α IL-6 IL-10 TGF-β MMP-2 MΦ (%) (A.U.) (A.U.) (A.U.) (A.U.) (A.U.) (A.U.) (A.U.) C57 MI 5.6±0.9 (8) 0.5±0.2 (3) 1.7±0.4 (3) 26±0.3 (3) 1.7±0.5 (3) 0.7±0.03 (3) 1.8±0.5 (3) 1±0.1 (5) Gal-3 KO MI 2.6±0.4* (8) 1.8±0.4*(8) 4.2±0.4* (8) 0.4±0.5* (8) 6.7±0.9 * (8) 2.8±0.3 * (8) 0.5±0.2 * (8) 2±0.4* (6) A.U.: Arbitrary units. In MR, YM1, TNF-α, IL-6, IL-10 and TGF-β represent mRNA expression. In MMP-2 represent gelatinolytic activity. Number of samples is shown between parentheses. After 1 week post-MI, LV end diastolic dimension was increased from 4.4±0.1 to 4.8±0.2* at the same time that ejection fraction (%) was significantly reduced from 47±2 to 38±3* in C57+MI (13) and Gal-3 KO+MI (16) respectively. Collagen concentration in the infarct zone was significantly reduced from 30±1.2% (6) to 17±0.5* % (8) in C57 and Gal-3 KO respectively. Conclusion(s) Gal-3 is an essential regulatory factor for the early wound healing since it regulates the dynamics of the reparative process through the phenotypic profile of MΦ, the pro- and anti-inflammatory cytokines expression and fibrosis along the temporal evolution of MI in mice. The deficit of Gal-3 diminished the infiltration of MΦ altering its phenotypic polarization and consequently, the dynamics of the wound healing as well as aggravating the functional and structural evolution of cardiac remodeling. Acknowledgement/Funding Argentine Agency for Promotion of Science and Technology (PICT 2014-2320), University of Buenos Aires (UBACyT 20020170100619BA)

Abstract 61: Dendritic Cell Regulates Monocyte/Macrophage Polarization and Inflammatory Response After Myocardial Infarction in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Atsushi Anzai ◽  
Toshihisa Anzai ◽  
Keiichi Fukuda
Keyword(s):  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Adoptive Transfer ◽  
Diphtheria Toxin ◽  
Macrophage Polarization ◽  
Healing Process ◽  
Left Ventricular ◽  
Endothelial Cell Proliferation ◽  
Control Group ◽  
Lv Function

Inflammation and immune responses are integral components in the healing process after MI. We previously reported dendritic cell (DC) infiltration in the infarcted heart. However, the precise contribution of DC in postinfarction healing is unclear. Bone-marrow (BM) cells from CD11c-diphtheria toxin receptor/GFP transgenic mice were transplanted into lethally irradiated WT recipient mice. After reconstitution of BM-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and MI was created by left coronary ligation. CD11c + GFP + DCs expressing CD11b and MHC class II were recruited into the heart, peaking on day 7 after MI in control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as IL-1β, IL-18 and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of MMP9 activity, and diminished expression level of IL-10 and endothelial cell proliferation following MI compared with control group. In vivo and in vitro analyses revealed that DC-ablated infarcts had an enhanced capacity of monocytes/macrophages recruitment. Among these cells, augmented infiltration of proinflammatory Ly6C high monocytes and F4/80 + CD206 - M1 macrophages, and conversely impaired recruitment of anti-inflammatory Ly6C low monocytes and F4/80 + CD206 + M2 macrophages in the infarcted myocardium were identified in DC-ablated group than in control group. To confirm these results, adoptive transfer experiment was performed. BM cells from WT mice were cultured with recombinant mouse GM-CSF for 6 days and CD11c + BMDCs were then positively collected by magnetic sorting. We confirmed that intravenously injected CFSE-labeled BMDCs reached infarcted zone. Adoptive transfer of BMDCs into DC-depleted mice restored LV function and negated the increases of inflammatory Ly6C high monocytes and myocardial MMP-9 activity following MI. In conclusion, dendritic cell is a potent immunoprotective regulator during the postinfarction healing process, via controlling monocyte/macrophage homeostasis.

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