Immune cell β2-adrenergic receptors contribute to the development of heart failure

Immune cell β2-adrenergic receptors (β2ARs) are important for proinflammatory macrophage infiltration to the heart in a chronic isoproterenol administration model of heart failure. Mice lacking immune cell β2AR have decreased immune cell infiltration to their heart, primarily proinflammatory macrophage populations. This decrease culminated to decreased cardiac injury with lessened cardiomyocyte death, decreased interstitial fibrosis and hypertrophy, and improved function demonstrating that β2AR regulation of immune responses plays an important role in the heart’s response to persistent βAR stimulation.

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Novel mechanism in cardiac injury: immune checkpoints

European Heart Journal ◽

10.1093/ehjci/ehaa946.3625 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E.M Screever ◽

M.L Axelrod ◽

M.A Blair ◽

D.Z Trykall ◽

J.V Barnett ◽

...

Keyword(s):

Immune Checkpoint ◽

Troponin I ◽

Immune Cell ◽

Cardiac Injury ◽

Cell Infiltration ◽

Immune Checkpoints ◽

Funding Source ◽

Immune Cell Infiltration ◽

Isolated Cardiomyocytes

Abstract Background Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis. Purpose The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury. Methods We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I. Results Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p<0.007). No differences were seen in immune cell infiltration, troponin I and ANP levels and echocardiography. Pdcd1−/-Ctla4+/+ and Pdcd1−/−Ctla4+/− mice showed a decrease in immune cell infiltration. Conclusions Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

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Abstract 482: Beta-catenin Activation in Cardiac Fibroblasts Modulates the Immune Micro-environment to Promote Fibrosis and Heart Failure Following Chronic Injury

Circulation Research ◽

10.1161/res.127.suppl_1.482 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Meiling Melzer ◽

Dina Hassan ◽

David Beier ◽

Pampee P Young ◽

Sarika Saraswati

Keyword(s):

Heart Failure ◽

Wnt Signaling ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Diastolic Heart Failure ◽

Expression Patterns ◽

Beta Catenin ◽

Chronic Injury ◽

Reactive Fibrosis

Almost 6.5 million people in United States suffer from heart failure (HF). Diastolic HF following non-ischemic cardiac insult is a progressive condition with limited effective therapies underscoring the urgency to invest in identifying novel therapeutic targets for treatment. Reactive fibrosis in response to pathological stress is one of the major causes of diastolic HF. Emerging data suggest an association of systemic inflammation with reactive fibrosis and HF. Canonical Wnt/beta-catenin signaling has been linked to HF and fibrosis with limited understanding of the precise cellular and molecular mechanism. We utilized thoracic aortic constriction (TAC), a well-defined model of HF, to study Wnt signaling mediated reactive fibrosis. TAC was induced in a transgenic mouse model with stabilized beta-catenin (Wnt signaling) in fibroblasts (Bcat/Postn). Wnt activation following TAC resulted in increased maladaptive reactive fibrosis, HF marker ANP, and cardiac hypertrophy with preserved Ejection Fraction (pEF) suggesting Wnt-mediated progression of diastolic heart failure with pEF. TAC also resulted in increased macrophage activation and recruitment of CD8+ cytotoxic T-cells. In vitro co-culture of Wnt3a-overexpressing fibroblasts with activated myeloid cells promoted fibroblast proliferation and collagen synthesis. Therefore, we hypothesize that Wnt signaling activation promotes interstitial fibrosis via recruitment of specific inflammatory cells. Genomic analysis further supports this by demonstrating distinct chemokine gene expression patterns in fibroblasts resulting from Wnt activation in these injury models. Our future goal is to elucidate the role of Wnt signaling in modulating the fibroblast-immune cell crosstalk in modulating interstitial fibrosis induced diastolic HFpEF. Currently, there is no approved therapy to specifically target reactive fibrosis to avert diastolic dysfunction. Our study is aiming to identify targetable cellular and molecular players that improve, prevent or avert reactive fibrosis mediated HFpEF in order to reduce the incidence and severity of pathology resulting from HF.

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VCAM1 expression in the myocardium is associated with the risk of heart failure and immune cell infiltration in myocardium

Scientific Reports ◽

10.1038/s41598-021-98998-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tongyu Wang ◽

Jiahu Tian ◽

Yuanzhe Jin

Keyword(s):

Heart Failure ◽

Adhesion Molecule ◽

Immune Regulation ◽

Immune Cell ◽

Enrichment Score ◽

Cell Infiltration ◽

Rna Modification ◽

Immune Cell Infiltration ◽

Lasso Regression ◽

Predicting Model

AbstractIschemic heart disease (IHD) and dilated cardiomyopathy (DCM) are the two most common etiologies of heart failure (HF). Both forms share common characteristics including ventricle dilation in the final stage. Immune mechanisms in HF are increasingly highlighted and have been implicated in the pathogeneses of IHD and DCM. A better understanding of adhesion molecule expression and correlated immune cell infiltration could enhance disease detection and improve therapeutic targets. This study was performed to explore the common mechanisms underlying IHD and DCM. After searching the Gene Expression Omnibus database, we selected the GSE42955, GSE76701, GSE5406, GSE133054 and GSE57338 datasets for different expressed gene (DEGs) selection and new cohort establishment. We use xcell to calculate immune infiltration degree, ssGSEA and GSEA to calculate the pathway and biological enrichment score, consensus cluster to identify the m6A modification pattern, and LASSO regression to make risk predicting model and use new combined cohort to validate the results. The screening stage revealed that vascular cell adhesion molecule 1 (VCAM1) play pivotal roles in regulating DEGs. Subsequent analyses revealed that VCAM1 was differentially expressed in the myocardium and involved in regulating immune cell infiltration. We also found that dysregulated VCAM1 expression was associated with a higher risk of HF by constructing a clinical risk-predicting model. Besides, we also find a connection among the m6A RNA modification ,expression of VCAM1 and immune regulation. Those connection can be linked by the Wnt pathway enrichment alternation. Collectively, our results suggest that VCAM-1 have the potential to be used as a biomarker or therapy target for HF and the m6A modification pattern is associated with the VCAM1 expression and immune regulation.

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Abstract 81: Absence of Macrophage microRNA-155 Affects Cardiac Metabolic and Inflammatory Remodeling Following Diabesotension and Protects Against Development of Heart Failure

Circulation Research ◽

10.1161/res.119.suppl_1.81 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Monika Rech ◽

Kristiaan Wouters ◽

Julie Lecomte ◽

Nicole Bitsch ◽

Stephane Heymans ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Adipose Tissue ◽

Cardiac Dysfunction ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Uncoupling Protein ◽

Chow Diet ◽

Low Grade ◽

Cardiac Inflammation

The co-existence of diabetes, obesity, hypertension - diabesotension - is a major burden in western societies and often culminates into heart failure (HF). Diabesotension is associated with a chronic status of low-grade inflammation, involving macrophage infiltration into adipose and cardiac tissues, local activation of inflammatory pathways and concomitant insulin-resistance. We showed that the microRNA miR-155 is a powerful modulator of hypertension-induced cardiac inflammation and HF. Here we hypothesize that absence of miR-155 in macrophages protects against adipose tissue and cardiac inflammation during diabesotension and thereby prevents insulin resistance and cardiac dysfunction. Male C57Bl/6J mice received a bone marrow transplantation of miR-155 WT (n=30) or miR-155 KO (n=30) donors with same genetic background. High fat (HFD; n=22/gr) or chow diet (n=8/gr) was given for 20 weeks. An HFD subgroup was subjected to pressure overload by angiotensin II (1.5mg/kg/d) for 4 weeks (HFD+PO; n=12/gr). Glycaemia, glucose tolerance test, cardiac MRI were performed after 16 and/or 20 weeks. Organs were stored for histology, RNA and FACS analysis. After 16 weeks of HFD, body weight (+11% WT; +14% KO; p<0.05) and glycaemia (+16% WT; +18% KO; p<0.05) increased compared to chow diet animals in both genotypes, confirming the status of obesity and pre-diabetes. Absence of macrophage miR-155 protected HFD-mice from glucose intolerance (at T15: WT 25.08; KO 18.15 mmol/L; p<0.05), suggesting that adipose tissue macrophages might contribute to insulin resistance. In addition, HFD+PO caused mild systolic dysfunction in WT but not in miR-155 KO animals compared to control (ejection fraction: -19% WT, p<0.05; -7% KO, n.s.). While cardiac interstitial fibrosis was not affected by absence of macrophage miR-155, cardiac CD45-positive leukocyte infiltration upon HFD+PO was abrogated. HFD+PO-induced cardiac expression of two PPAR-dependent metabolic genes, angiopoietin-like 4 and uncoupling protein 3, is repressed in the absence of macrophage miR-155. Our data suggest that macrophage miR-155 plays a role in the development of insulin resistance and cardiac dysfunction, possibly by affecting local immune cell function and metabolic programming.

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Elevated Myocardial VCAM1 Expression is Associated with Higher Risk of Dilated Cardiomyopathy or Ischemic Heart Disease-caused Heart Failure and Higher Immune Infiltration in Failing Myocardium

10.21203/rs.3.rs-658306/v1 ◽

2021 ◽

Author(s):

Tongyu Wang ◽

Jiahu Tian ◽

Yuanzhe Jin

Keyword(s):

Heart Failure ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Dilated Cardiomyopathy ◽

Adhesion Molecule ◽

Immune Cell ◽

Ischemic Heart ◽

Cell Infiltration ◽

Intercellular Adhesion Molecule ◽

Immune Cell Infiltration

Abstract Background. Ischemic heart disease (IHD) and dilated cardiomyopathy (DCM) are the two most common etiologies of heart failure (HF). Both forms share common characteristics including ventricle dilation in the final stage. Immune mechanisms in HF are increasingly highlighted and have been implicated in the pathogeneses of IHD and DCM. A better understanding of adhesion molecule expression and correlated immune cell infiltration could enhance disease detection and improve therapeutic targets. Objective. This study was performed to explore the common mechanisms underlying IHD and DCM.Methods. After searching the Gene Expression Omnibus database, we selected the GSE42955 and GS57338 datasets for analysis, which contain 29 and 313 samples, respectively. Results. The screening stage revealed that vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) play pivotal roles in regulating DEGs. Subsequent analyses revealed that VCAM1 was differentially expressed in the myocardium and involved in regulating immune cell infiltration. We also found that dysregulated VCAM1 expression was associated with a higher risk of HF by constructing a clinical risk-predicting model. Conclusions. Collectively, our results suggest that VCAM-1 could be used as a biomarker or therapy target for HF.

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