scholarly journals Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Kuljeet Kaur ◽  
Francisco E. Velázquez ◽  
Marina Anastasiou ◽  
Njabulo Ngwenyama ◽  
Sasha Smolgovsky ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Transmembrane Protein ◽  
Myeloid Cells ◽  
Pressure Overload ◽  
Cardiac Inflammation ◽  
Adaptive Immune Cells

Sialomucin CD43 is a transmembrane protein differentially expressed in leukocytes that include innate and adaptive immune cells. Among a variety of cellular processes, CD43 participates in T cell adhesion to vascular endothelial cells and contributes to the progression of experimental autoimmunity. Sequential infiltration of myeloid cells and T cells in the heart is a hallmark of cardiac inflammation and heart failure (HF). Here, we report that CD43−/− mice have improved survival to HF induced by transverse aortic constriction (TAC). This enhanced survival is associated with improved systolic function, decreased cardiac fibrosis, and significantly reduced T cell cardiac infiltration in response to TAC compared to control wild-type (WT) mice. Lack of CD43 did not alter the number of myeloid cells in the heart, but resulted in decreased cardiac CXCL10 expression, a chemoattractant for T cells, and in a monocyte shift to anti-inflammatory macrophages in vitro. Collectively, these findings unveil a novel role for CD43 in adverse cardiac remodeling in pressure overload induced HF through modulation of cardiac T cell inflammation.

Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts & Contribute to Pressure Overload Induced Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Ane Salvador ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Robert Blanton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Effector T Cell ◽  
Naïve T Cells

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.

Abstract 408: The Role of the Chemokine Receptor CXCR3 - Integrin Lymphocyte Function Associated Antigen 1 (LFA1) - Intercellular Adhesion Molecule 1 (ICAM1) Axis in T Lymphocyte Mediated Cardiac Inflammation in Pressure Overload Induced Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Ane Miren Salvador ◽  
Tania Nevers ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Pilar Alcaide
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Lymphocyte Function ◽  
Cell Recruitment ◽  
Mouse Tissues

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans and mice with increased circulating chemokines CXCL9, CXCL10 and CXCL11. Expression of their receptor, CXCR3, in circulating T cells is associated with disease progression in HF patients. We recently published that ICAM1 is significantly upregulated in the LV endothelium and contributes to the progression of HF by regulating T cell recruitment to the LV in a mouse model of pressure overload (PO) induced HF. As CXCR3 can signal to integrins upon chemokine recognition and induce T cell adhesion to endothelial cells under flow conditions in vitro , we hypothesize that chemokine signaling through CXCR3 contributes to LV T cell recruitment and regulates integrin dependent adhesion to ICAM1 in PO induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM1 -/- mice, cardiac fibroblasts (CFB) isolated from adult C57/BL6 mice, flow cytometry and qPCR in mouse tissues and in cells cultured in vitro . The LV expression of CXCL9, 10 and 11 was upregulated in WT mice in response to 2 and 4 weeks TAC as compared to Sham, correlating with ICAM1, IL-6 and IL-1β upregulation and increased CXCR3+ T cell LV infiltration. In vitro , CFB cultured with CXCR3+ T cells or with their culture supernatants, induced CXCL9, 10 and 11, as compared to control media cultured CFB, suggesting CFB are a source of these chemokines under stress. 4 weeks post TAC in WT mice, LV recruited CXCR3+ T cells, as well as mediastinal lymph node and circulating CXCR3+ lymphocytes expressed higher levels of the integrin LFA1, the main ligand of ICAM1, than CXCR3- T cells. The same pattern was observed in systemic CXCR3+ T cells in ICAM1 -/- mice, which, in contrast to WT mice, had reduced LV infiltrated T cells. Conclusion: Our data supports a CXCR3-LFA1-ICAM1 axis being involved in non- ischemic HF. Further studies will determine the CXCR3 ligands triggering T cell LFA1 activation through CXCR3 and whether this mechanism regulates the pathology of non- ischemic HF via ICAM-1 mediated adhesion.

Abstract P480: Myeloid YAP Inhibition Improves Cardiac Phenotype During Pressure Overload Stress

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Jamie J Francisco ◽  
Yu Zhang ◽  
Yasuki Nakada ◽  
Peiyong Zhai ◽  
Dominic Del Re
Keyword(s):  
Gene Expression ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Myeloid Cells ◽  
Pressure Overload ◽  
Inflammatory Gene Expression ◽  
Cardiac Inflammation ◽  
Inflammatory Gene ◽  
Raw264.7 Macrophages ◽  
Cardiac Phenotype

Inflammation is a component of cardiovascular disease and is thought to contribute to cardiac dysfunction in ischemic and non-ischemic models of heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP), a transcriptional co-factor, in modulating cardiac inflammation and remodeling after myocardial infarction. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition is cardioprotective. PO in mice elicits an immune response characterized by infiltration of myeloid cells that precedes cardiac dysfunction. Myeloid cells isolated from the heart after 7d PO showed evidence of increased YAP activity. Myeloid-specific YAP knockout mice (YAP F/F ;LysM Cre ) were subjected to PO stress. After 4 weeks, cardiac hypertrophy was similar between YAP KO mice and controls. However, systolic dysfunction, cardiac fibrosis, and indicators of pathological remodeling were all attenuated in YAP KO mice compared to controls. Additionally, inflammatory gene expression and macrophage infiltration to the myocardium were significantly attenuated in YAP KO mice after PO, indicating reduced inflammation compared to controls. Experiments using RAW264.7 macrophages and primary bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that increased YAP expression enhanced, while YAP suppression attenuated, inflammatory gene expression. The inflammasome is a multiprotein complex and important facilitator of cytokine processing that mediates inflammation in the PO heart. We observed attenuated inflammasome priming and function in YAP deficient BMDMs, as well as in YAP KO hearts following PO, indicating disruption of inflammasome induction. Together these data implicate YAP as an important mediator of inflammasome function and cardiac inflammation during PO stress and suggest that selective inhibition of YAP in the myeloid compartment may prove a novel therapeutic target in non-ischemic heart disease.

Abstract 406: Interaction of T Cells From Non-ischemic Heart Failure Patients With the Activated Vascular Endothelium is Dependent on Intercellular Adhesion Molecule-1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Francisco Velazquez ◽  
Ane Salvador ◽  
Navin Kapur ◽  
Pilar Alcaide
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
T Cell ◽  
Vascular Endothelium ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
High Affinity

Background: Increasing evidence supports a role for inflammation in the pathogenesis of chronic heart failure (HF). Our previous studies demonstrate that T cell recruitment to the heart contributes to the progression of non-ischemic pressure overload induced HF. However, clinical data describing T cell dependent mechanisms contributing to the etiology of this disorder remains unknown. We hypothesized that non-ischemic HF activates human T cells resulting in increased adhesion to the vascular endothelium and recruitment to the heart through mechanisms involving specific endothelial adhesion molecules. Methods and Results: We used T cells from non-ischemic HF patients and non-HF controls as well as left ventricular (LV) tissue from end stage HF after LV assisted device (LVAD) support. Using FACS analysis we found that systemic T cells are significantly elevated in HF patients compared to controls (p<0.05), including Th1, Th17, and Treg cells. Immunohistochemistry analysis revealed that CD3+ and CD4+ T cells infiltrate the LV of HF subjects which were not observed in control. To evaluate the mechanisms through which T cells interact with the vasculature and potentially infiltrate the heart, we used in vitro real time video microscopy under shear flow conditions and found that T cells from HF patients firmly adhered to TNF[[Unsupported Character - Symbol Font &#61537;]] activated HUVECS. Further analysis indicated that HF T cells adhered to ICAM-1, but not to VCAM-1 in higher numbers than control T cells. The surface expression levels of the integrin ligands for VCAM-1 and ICAM-1 (VLA-4 and LFA-1 respectively) were similar between both groups, however, HF T cells exhibited a highly polarized phenotype on ICAM-1 (p<0.005 vs control), suggesting LFA-1 is in its high affinity conformation in HF T cells. Conclusions: Our findings suggest that T cells are activated in non-ischemic HF and have high affinity for the activated endothelium through mechanisms involving ICAM-1- LFA-1 adhesion. Future studies will evaluate the mechanisms regulating LFA-1 activation in HF T cells and their contribution to cardiac remodeling.

Abstract 171: T Cell Mediated Immune Responses Regulate Cardiac Remodeling and Survival in Pressure Overload Induced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Pilar Alcaide ◽  
Tania Nevers ◽  
Ane Salvador ◽  
Anna Grodecki-Pena ◽  
Andrew Knapp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Immune Response ◽  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
T Cell Response

Background: Clinical data support that inflammation and the improper regulation of the immune response are intimately associated with Heart Failure (HF), however, the type of immune response involved and whether it regulates cardiac remodeling remains largely unexplored. We hypothesize that T cell mediated immune responses and their recruitment into the heart influence cardiac remodeling and contribute to the pathogenesis of pressure overload induced HF. Methods and Results: Using quantitative flow cytometry we found that T cells infiltrated the heart as Wild-type mice (WT) developed systolic dysfunction and LV hypertrophy in response to transverse aortic constriction (TAC) (p<0.01 TAC vs Sham). Real time imaging demonstrated that T cells from TAC mice adhered to activated heart endothelial cells in higher numbers than T cells from Sham mice under physiological flow conditions in vitro (P<0.05) indicating a systemic T cell activation to pressure overload induced by TAC. Similarly, circulating T cells from patients with HF adhered more to activated human umbilical vein endothelial cells (HUVEC) than T cells from healthy volunteers. Based on these findings, we performed similar TAC studies in T cell deficient mice (TCRα -/- ). In contrast with WT TAC mice, TCRα -/- had preserved LV systolic and diastolic function (p<0.01) determined by echocardiography and hemodynamic studies, reduced LV fibrosis (p<0.001) and TGFβ1, collagen Iα and αSMA gene expression (p<0.05), and reduced LV hypertrophy and gene expression of ANP and BNP (p<0.05), but unaltered expression of SerCA. Remarkably, TCRα -/- had improved survival after 4 weeks of TAC [100%(16/16) TCRα -/- vs 73.7%(14/19) WT, p=0.023]. Ongoing studies will determine the mechanisms regulating T cell recruitment into the heart, the type of T cell response involved and its contribution to pathological remodeling of the heart. Conclusion: Our studies demonstrate that T cell immune responses and their recruitment into the LV contribute to the pathogenesis of pressure overload induced HF by mechanisms involving T cell regulation of cardiac hypertrophy and fibrosis, and open a window to develop novel therapeutic strategies to improve the structural, functional and molecular deficits of the failing heart.

Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jian Cao ◽  
John A McClung ◽  
Shailendra P Singh ◽  
Lars Bellner ◽  
Maayan Waldman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Control Group ◽  
Protein Markers ◽  
Obesity And Diabetes

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

The costimulatory activity of Tim-3 requires Akt and MAPK signaling and its recruitment to the immune synapse

2021 ◽  
Vol 14 (687) ◽  
pp. eaba0717
Author(s):  
Shunsuke Kataoka ◽  
Priyanka Manandhar ◽  
Judong Lee ◽  
Creg J. Workman ◽  
Hridesh Banerjee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Inhibitory Protein ◽  
Immune Synapse

Expression of the transmembrane protein Tim-3 is increased on dysregulated T cells undergoing chronic activation, including during chronic infection and in solid tumors. Thus, Tim-3 is generally thought of as an inhibitory protein. We and others previously reported that under some circumstances, Tim-3 exerts paradoxical costimulatory activity in T cells (and other cells), including enhancement of the phosphorylation of ribosomal S6 protein. Here, we examined the upstream signaling pathways that control Tim-3–mediated increases in phosphorylated S6 in T cells. We also defined the localization of Tim-3 relative to the T cell immune synapse and its effects on downstream signaling. Recruitment of Tim-3 to the immune synapse was mediated exclusively by the transmembrane domain, replacement of which impaired the ability of Tim-3 to costimulate T cell receptor (TCR)–dependent S6 phosphorylation. Furthermore, enforced localization of the Tim-3 cytoplasmic domain to the immune synapse in a chimeric antigen receptor still enabled T cell activation. Together, our findings are consistent with a model whereby Tim-3 enhances TCR-proximal signaling under acute conditions.

scholarly journals CD4 + T Cells Promote the Transition From Hypertrophy to Heart Failure During Chronic Pressure Overload

Circulation ◽  
2014 ◽  
Vol 129 (21) ◽  
pp. 2111-2124 ◽  
Author(s):  
Fanny Laroumanie ◽  
Victorine Douin-Echinard ◽  
Joffrey Pozzo ◽  
Olivier Lairez ◽  
Florence Tortosa ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
Cd4 T Cells ◽  
Pressure Overload

P3527Echocardiographic assessment of the right ventricle in chronic heart failure with focus on patients with atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Majos ◽  
A Kraska ◽  
I Kowalik ◽  
E Smolis-Bak ◽  
H Szwed ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Systolic Function ◽  
Pressure Overload ◽  
Ventricular Ejection Fraction ◽  
Rv Pacing ◽  
The Right ◽  
Rv Function

Abstract Background Assessment of the right ventricle (RV) in heart failure (HF) is challenging and requires applicable methods and parameters. Atrial fibrillation (AF) is a common and clinically significant arrhythmia in 30–50% of HF patients. Assessment of the RV function in patients with AF is problematic. Still little is known about RV function in HF and AF patients. The aim of the study was to assess RV function in HF with focus on AF patients. Methods Patients with HF of ischemic etiology, NYHA II-III, LVEF ≤40%, with AF and sinus rhythm (SR), underwent two- and three- dimensional echocardiography (2DE and 3DE) for assessment of the RV with use of multiple parameters. The RV was examined for: linear dimensions, end-diastolic and end-systolic areas adjusted to body surface area (RV EDA and RV ESA/BSA) and end-diastolic and end-systolic volumes adjusted to lean body mass (RV EDV and RV ESV/LBM) to reflect volume overload and in terms of right ventricular pressure (RVSP) as an index of pressure overload. RV systolic function was assessed with 2DE: tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RV FAC), tricuspid lateral annular systolic velocity (s') and 3DE parameters: right ventricular ejection fraction (RVEF) and free wall right ventricular longitudinal strain (FW RVLS). Also, TAPSE/RVSP parameter was included. Results The study included 126 patients: 94 with AF and 32 with SR. Within the AF group 28 patients were treated medically, 41 had RV pacing (pacemaker or an implantable cardioverter-defibrillator, ICD) and 25 had cardiac resynchronisation therapy (CRT). In comparison with SR group AF patients had: larger RV inflow tract dimension (4.49±0.85 vs. 3.95±0.72 cm; p=0.0017), RV EDA/BSA (12.7±3.9 vs. 11.1±3.0 cm2/m2; p=0.0358) and RV ESA/BSA (8.0±3.0 vs. 6.7±2.4 cm2/m2; p=0.0226). Similarly, patients with AF had greater RV volumes in 3DE than patients with SR: RV EDV/LBM (1.82±0.60 vs. 1.61±0.38ml/kg, p=0.0267) and RV ESV/LBM (1.11±0.40 ml/kg vs. 0.81±0.28, p<0,0001). Also, in patients with AF right ventricular systolic pressure (RVSP) was higher (40.8±10.2 vs. 34.0±8.1 mmHg, p=0,0010). No differences in TAPSE and RVFAC were found but the relation TAPSE/RVSP was higher in AF than in SR group (0.51±0.21 vs. 0.65±0.24 cm/mmHg; p=0.0046). Also, in AF patients in comparison to SR group some parameters had worse values: s' (9.7±2.31 vs. 12.1±3.83, p=0.014), RVEF (37.2±7.3 vs. 48.2±7.5, p<0.0001 and FW RVLS (−18.3±4.6 vs. −23.9±4.23%, p<0,0001). Within the AF group no significant differences in studied variables depending on RV pacing or CRT were found. Conclusions Larger volumes and higher pressure overload of the RV were observed in patients with AF in comparison to SR. Systolic function of the RV seems to be more depressed in AF compared to SR patients with systolic heart failure. Further research in larger groups is required to identify the most applicable and valuable methods of RV evaluation.

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