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Hematopoietic Loss of Y Chromosome Leads to Cardiac Fibrosis and Dysfunction and is Associated with Death due to Heart Failure [bulkRNAseq_HeartNeutrophils]

ABSTRACT: Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and a variety of age-related diseases in men, but causal and mechanistic relationships have yet to be established. Here it is shown that mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including a progressive decline in cardiac function. Accelerated cardiac dysfunction and fibrosis were also observed in younger mice subjected to a pressure-overload model of heart failure. Bone marrow-derived, cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic and less inflammatory phenotype. Treatment with a TGFb1 neutralizing antibody led to greater amelioration of heart failure in mice reconstituted with mLOY compared to wild-type bone marrow. Consistent with these data, a prospective study in men revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY contributes to heart failure in men.

ORGANISM(S): Mus musculus

PROVIDER: GSE205089 | GEO | 2022/06/02

REPOSITORIES: GEO

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Hematopoietic Loss of Y Chromosome Leads to Cardiac Fibrosis and Dysfunction and is Associated with Death due to Heart Failure

Project description:Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and a variety of age-related diseases in men, but causal and mechanistic relationships have yet to be established. Here it is shown that mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including a progressive decline in cardiac function. Accelerated cardiac dysfunction and fibrosis were also observed in younger mice subjected to a pressure-overload model of heart failure. Bone marrow-derived, cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic and less inflammatory phenotype. Treatment with a TGFb1 neutralizing antibody led to greater amelioration of heart failure in mice reconstituted with mLOY compared to wild-type bone marrow. Consistent with these data, a prospective study in men revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY contributes to heart failure in men.

2022-08-01 | GSE204732 | GEO

Hematopoietic Loss of Y Chromosome Leads to Cardiac Fibrosis and Dysfunction and is Associated with Death due to Heart Failure [bulkRNAseq_WholeBloodNeutrophils]

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Hematopoietic Loss of Y Chromosome Leads to Cardiac Fibrosis and Dysfunction and is Associated with Death due to Heart Failure [bulkRNAseq_HeartMacrophages]

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Mosaic loss of chromosome Y leads to clonal hematopoiesis and promotes leukemogenesis in mice

Project description:Mosaic loss of chromosome Y (mLOY) is the most frequent chromosome alternation in the blood cells of aging adult male and is closely associated with AML, so we designed experiments to explore the mechanism. Bulk RNA sequencing was performed with AML1-ETO;sgSsty2/sgScramble;Trp53-/- Bone Marrow in vivo and sgSsty2/sgSsty1/sgScramble;Trp53-/- c-kit+ HSPCs in vitro. And our study demonstrates that mLOY is a functional driver for clonal hematopoiesis and leukemogenesis. KDM5D, a gene mediated H3K4 demethylation and located on both human and mouse chromosome Y, we wondered whether KDM5D could be a critical gene responsible for the pathology of mLOY. So bulk RNA sequencing was performed with sgKdm5d/sgScramble;Trp53-/- Bone marrow in vivo and Trp53-/- c-kit+ HSPCs in vitro to explore the mechanism of Kdm5d in mLOY.

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Bone marrow macrophage derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

Project description:Levels of Glyco Protein Non-metastatic Melanoma protein B (GPNMB), a type I transmembrane protein, originally identified in non-metastatic melanomas has been shown to be strongly associated with human heart failure. However, the role of GPNMB in modulation of cardiac injury and cardiac function remains unclear. We analyzed human cardiac global gene expression data sets and observed increased GPNMB expression in failing hearts. In murine hearts after myocardial infarction (MI), we showed that GPNMB expression increased by an order of magnitude. Lineage tracing and bone marrow transplantation experiments demonstrated that bone marrow macrophages were the primary source of GPNMB in the injured heart. Using genetic loss of function approaches, we demonstrate that animals deficient in GPNMB exhibited significantly higher mortality, cardiac rupture and developed rapid post infarct LV dysfunction. Conversely gain of function approaches by increasing circulating GPNMB levels by viral delivery led to augmentation of post MI heart function. Single cell transcriptomics demonstrated pleiotropic effects of GPNMB on gene expression of myocytes and non-myocytes leading to enhanced myocyte contraction and decreased fibroblast activation. Using chemical cross-linking studies and immunoprecipitation studies, we identified the orphan receptor GPR39 as a receptor for circulating GPNMB. In animals deficient in GPR39, GPNMB failed to deliver beneficial effects on post infarct heart function. Taken together, these observations demonstrate that bone marrow macrophage derived GPNMB plays a pivotal role in cardiac repair following myocardial infarction, by mediating its pleiotropic effects in part via the orphan receptor GPR39

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Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy

Project description:Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n=1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

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Cardiac gene expression profiling of apoE-deficient mice receiving heart failure treatment with the anti-ischemic drug ranolazine

2010-12-03 | GSE25767 | GEO

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

Project description:Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

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