Mus musculus
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ABSTRACT:
PROVIDER: PRJNA146569 | ENA |
REPOSITORIES: ENA
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Project description:Insulin-like growth factor (IGF1R) signalling has been implicated to play an important role in regulation of cardiac growth, hypertrophy and contractile function, and has been linked to the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3β-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated β-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts. Four samples of each group: the control group, positive for Cre recombinase, but negative for the floxed IGF-1R and the experimental group with double transgenic mice (merCremer/+ IGFloxP/IGFloxP).
2012-07-31 | E-GEOD-32936 | biostudies-arrayexpress
Project description:Insulin-like growth factor (IGF1R) signalling has been implicated to play an important role in regulation of cardiac growth, hypertrophy and contractile function, and has been linked to the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3β-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated β-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts.
2012-08-01 | GSE32936 | GEO
Project description:Age-related changes in cardiac homeostasis lead to myocardial dysfunction and cardiovascular diseases, which predict the healthspan of ageing. Age is a prominent risk factor for cardiac-related diseases. During ageing, the heart undergoes structural remodeling (increased cardiac weight and myocardial fibrosis) and functional decline (reduced diastolic and systolic functions), causing vulnerability of the heart to extra stress. Consequently, these pathological changes lead to increased cardiovascular mortality and morbidity in elderly adults. The underlying mechanism of cardiac ageing remains largely unexplored; and no pharmacological agent is currently available to improve or delay cardiac senescence.
2025-01-29 | GSE200741 | GEO
Project description:VEGF family members are important regulators of vascular functions. Promoting VEGFA signalling in aged mice has been shown to delay various aging phenotypes and extend the survival of aged mice. Although there is profound knowledge on functions of VEGFA, VEGFB has not been investigated in the context of cardiac aging. Our RNA data of aged mouse hearts revealed significant downregulation of Vegfb in the heart, specifically in endothelial cells and cardiomyocytes, while VEGFB expression was reduced in endothelial cells, fibroblasts and cardiomyocytes in aged human hearts. By contrast, VEGFB expression was exclusively reduced in cardiomyocytes of patients with cardiac hypertrophy. Hence, we investigated whether Vegfb gene therapy can revert age-dependent cardiac pathologies. We overexpressed Vegfb186, the soluble VEGFB isoform, via AAV9 vector transduction into 18-month-old C57Bl/6J male mice. AAV9-Vegfb treatment prevented progression age-related diastolic dysfunction and decreased cardiac fibrosis. We further found a rescue of aging-related left ventricular denervation in the hearts of AVV9-Vegfb treated old mice which was associated with an increase in heart rate variability. However, heart to body weight ratio and cardiomyocyte hypertrophy were increased in the AAV9-Vegfb treated mouse hearts, without alteration of cardiac systolic or diastolic function. Histological and transcriptomic analyses revealed that VEGFB186 induces compensatory cardiac hypertrophy which was accompanied by a rescued length-width-ratio, reduced fibrosis and the absence of cardiac inflammation. Cardiac single-nuclei RNA sequencing further suggested that AAV9-Vegfb treatment affects cardiac hypertrophy putatively via STAT3 which was validated in vitro. In conclusion, our data reveals that Vegfb overexpression partially reverses pathological alterations in the aging heart. Despite the overall improvement of the age-related cardiac phenotype, the AAV9-Vegfb-mediated induced cardiac hypertrophy which might reflect protective hypertrophy.
2024-11-30 | E-MTAB-14595 | biostudies-arrayexpress
Project description:Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Here, we quantified the phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome.
2022-04-23 | PXD025555 | Pride
Project description:Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends lifespan, while it exerts cardioprotective effects through reduction of cardiac hypertrophy and preservation of diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy, mitochondrial respiration and mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine failed to promote cardioprotection in mice lacking the autophagy-related gene Atg5 in cardiomyocytes. In Dahl salt-sensitive rats fed high-salt diet, a model for hypertension-induced congestive heart failure, spermidine reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. Finally, high dietary spermidine intake correlated with reduced blood pressure and a lower incidence of cardiovascular disease in humans. Our results suggest a novel and generic strategy against cardiovascular disease.
2016-11-13 | GSE86882 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2021-01-12 | GSE164609 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-02-08 | GSE144934 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-02-08 | GSE144933 | GEO
Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.
2020-07-01 | GSE151333 | GEO