ANTXR1/TEM8 Blockade Prevents Heart Failure through Suppression of TGF-β Signaling
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PROVIDER: PRJNA1107810 | ENA |
REPOSITORIES: ENA
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Project description:Heart disease, a leading cause of mortality worldwide, is in urgent need of improved therapies. Here, ANTXR1/TEM8, a transmembrane protein required for collagen uptake, was found to promote heart failure. In preclinical intervention studies, genetic disruption of Antxr1 prevented heart deterioration following acute myocardial infarction, a phenotype that was mirrored by treatment with ANTXR1 neutralizing antibodies. ANTXR1 pharmacologic blockade also improved heart function in models of pressure overload and obesity-induced heart disease with preserved ejection fraction. Exploratory studies to further unravel the mechanism, including single cell transcriptomics, revealed a striking ANTXR1-antibody driven improvement in post-infarct scar formation followed by attenuation of late-stage, chronic TGFβ-mediated extracellular matrix remodeling. Thus, ANTXR1 function during heart failure is both maladaptive and druggable, providing promising new avenues for therapeutic intervention.
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Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
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Project description:Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3 deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-/- white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-/- adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-alpha1 expression. We observe significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta1 signaling protects mice from obesity, diabetes and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta1 activity might be an effective treatment strategy for obesity and diabetes. Smad3-/- and WT mice were fed with regular diet (RD) and high fat diet (HFD), and diet induced obese (DIO) mice were treated with IgG and anti-TGF-b1 antibody
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Project description:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by clonal expansion of myeloid cells, notably megakaryocytes (MKs), and aberrant cytokine production leading to bone marrow (BM) fibrosis and insufficiency. Current treatment options are limited. TGF-b1, a profibrotic and immunosuppressive cytokine, is involved in PMF pathogenesis. While all cell types secrete inactive, latent TGF-b1, only a few activate the cytokine via cell type-specific mechanisms. The cellular source of the active TGF-b1 implicated in PMF is not known. Transmembrane protein GARP binds and activates latent TGF-b1 on the surface of regulatory T lymphocytes (Tregs) and MKs or platelets. Here, we found increased expression of GARP in BM and spleen of mice undergoing PMF and tested the therapeutic potential of a monoclonal antibody that blocks TGF-b1 activation by GARP-expressing cells. GARP:TGF-b1 blockade reduced not only fibrosis, but also clonal expansion of transformed cells. Using mice carrying a genetic deletion of Garp in either Tregs or MKs, we found that the therapeutic effects of GARP:TGF-b1 blockade in PMF imply targeting GARP on Tregs. These therapeutic effects, accompanied by increased IFN-g signals in the spleen, were lost upon CD8 T cell depletion. Our results suggest that selective blockade of TGF-b1 activation by GARP-expressing Tregs increase a CD8 T cell-mediated immune reaction that limits transformed cell expansion, providing a novel approach that could be tested to treat patients with myeloproliferative neoplasms.
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Project description:Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
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Project description:The efficacy of costimulation blockade (CTLA4Ig/belatacept) in transplantation is reduced by an increased incidence of T cell-mediated rejection, which also persists after induction therapy with anti-thymocyte globulin (ATG). Herein, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between Tregs and effector T cells in the peripheral compartment, it had no such effect within cardiac allografts, which showed signs of inflammation. Neutralizing IL-6 alleviated inflammation, increased intragraft Treg frequencies long-term, and enhanced intragraft IL-10 and Th2 cytokine expression. IL-6 blockade together with ATG led to long-term, rejection-free heart graft survival under CTLA4Ig therapy. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.
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