Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart
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ABSTRACT:
PROVIDER: PRJEB72860 | ENA |
REPOSITORIES: ENA
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Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
2024-03-06 | E-MTAB-13841 | biostudies-arrayexpress
Project description:Background. Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods. In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results. We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of α smooth muscle actin in a TFGβ2 dependent mechanism. Conclusions. Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
2024-03-13 | E-MTAB-13833 | biostudies-arrayexpress
Project description:Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart (Bulk RNA-SEQ)
| PRJEB72833 | ENA
Project description:Tubulointerstitial fibrosis associated to chronic kidney disease represents a global healthcare problem. We showed previously that short and dysfunctional telomeres lead to interstitial renal fibrosis, however, the cell-of-origin of kidney fibrosis associated to telomere dysfunction was unknown to date. To identify the specific cell type responsible for this type of renal fibrosis, we induced telomere dysfunction by deleting the Trf1 telomere-binding factor both in renal fibroblasts and pericytes both in short-term and long-term life-long experiments in mice. Short-term Trf1 deletion in renal fibroblasts and pericytes was not sufficient to trigger kidney fibrosis. However, long-term persistent deletion of Trf1 in fibroblasts, triggered inflammation, cell cycle arrest, fibrogenesis, and vascular rarefaction. These cellular responses lead to macrophage-to-myofibroblast transition (MMT), Endothelial-to-mesenchymal transition (EndMT), and epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at humane-endpoint when deletion of Trf1 in fibroblasts was maintained throughout the lifespan of mice. In contrast, Trf1 deletion in pericytes did not lead to any kidney phenotypes both in short-term and long-term experiments.
2024-09-04 | GSE232874 | GEO
Project description:Despite the prevalence of pericytes amongst the microvasculature of the heart, the role of pericytes during ischemia-induced remodeling remains unclear. Using chondroitin sulfate proteoglycan 4 (Cspg4) lineage mouse reporters we observed pericytes migrating to the site of injury, expressing pro-fibrotic genes, and causing increased vessel leakage after myocardial infarction. Single cell RNA-sequencing of injured cardiac pericytes exhibited increased expression of genes related to vascular permeability, extracellular matrix production, basement membrane degradation and transforming growth factor-b (TGFb) signaling. Deletion of TGFb receptor 1 in Cspg4-expressing cells improved cardiac ejection fraction and reduced fibrosis post-MI. Whereas genetic ablation of Cspg4-expressing cells resulted in a rapid decline in cardiac function and increased vascular permeability following MI. Collectively, we show that cardiac pericytes participate in the post-fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate cardiac fibrosis.
2023-05-10 | GSE201947 | GEO
Project description:Pulmonary Fibrosis and Telomerase Dysfunction
| PRJNA779497 | ENA
Project description:Pulmonary Fibrosis and Telomerase Dysfunction
| PRJNA779498 | ENA
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO
Project description:Deletion of Tmem43 encoding nuclear membrane protein TMEM43, specifically in mouse cardiac myocytes leads to cardiac fibrosis and dysfunction. Temporal RNA-seq identified early and late trascriptomic changes and implicates TGFb1 in the pathogenesis of ACM caused by Tmem43 haploinsufficiency.
2021-02-26 | GSE147317 | GEO
Project description:Lung transplant outcomes in pulmonary fibrosis with and without telomere dysfunction
2021-07-22 | PRJEB46414 | EVA