Similar Datasets
Project description:As we age, structural changes contribute to progressive decline in organ function, which in the heart acts through poorly characterized mechanisms. Utilizing the rapidly aging fruit fly model with its significant homology to the human cardiac proteome, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age. Unlike other tissues and laminopathies, we observe decreasing nuclear size, while nuclear stiffness increases. Premature genetic reduction of Lamin C phenocopies aging’s effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find an adult-specific role for cardiac transcription factors and show that maintenance of Lamin C sustains their expression and prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.
2022-11-01 | GSE185967 | GEO
Project description:As we age, structural changes contribute to progressive decline in organ function, which in the heart acts through poorly characterized mechanisms. Utilizing the rapidly aging fruit fly model with its significant homology to the human cardiac proteome, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age. Unlike other tissues and laminopathies, we observe decreasing nuclear size, while nuclear stiffness increases. Premature genetic reduction of Lamin C phenocopies aging’s effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find an adult-specific role for cardiac transcription factors and show that maintenance of Lamin C sustains their expression and prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.
2022-11-01 | GSE185923 | GEO
Project description:As we age, structural changes contribute to progressive decline in organ function, which in the heart act through poorly characterized mechanisms. Taking advantage of the short lifespan and conserved cardiac proteome of the fruit fly, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age, coincident with decreasing nuclear size and increasing nuclear stiffness. Premature genetic reduction of Lamin C phenocopies aging's effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find a role for cardiac transcription factors in regulating adult heart contractility and show that maintenance of Lamin C, and cardiac transcription factor expression, prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating that age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction.
| S-EPMC9956937 | biostudies-literature
Project description:Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs
| PRJNA771560 | ENA
Project description:Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs [ATAC-Seq]
| PRJNA771372 | ENA
Project description:Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs [RNA-Seq]
| PRJNA771565 | ENA
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: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:It is known that there is an age-related progression in diastolic dysfunction, especially prevalent in postmenopausal women, who develop heart failure with preserved ejection fraction (HFpEF, EF > 50%). Mechanisms and therapies are poorly understood, but there are strong correlations between obesity and HFpEF. We have tested the hypothesis that P21-activated kinase-1 (PAK1) preserves cardiac function and adipose tissue homeostasis during aging in female mice. Previous demonstrations in male mice by our lab that PAK1 activity confers cardio-protection against different stresses formed the rationale for this hypothesis. Our studies compared young (3-6 months) and middle-aged (12-15 months) female and male PAK1 knock-out mice (PAK1-/-) and wild-type (WT) equivalent. Female WT mice exhibited increased cardiac PAK1 abundance during aging. By echocardiography, compared to young WT female mice, middle-aged WT female mice showed enlargement of the left atrium as well as thickening of posterior wall and increased left ventricular mass; however, all contraction and relaxation parameters were preserved during aging. Compared to WT controls, middle-aged PAK1-/- female mice demonstrated worsening of cardiac function involving a greater enlargement of the left atrium, ventricular hypertrophy, and diastolic dysfunction. Moreover, with aging PAK1-/- female mice, unlike male PAK1-/- mice, exhibited increased adiposity with increased accumulation of visceral adipose tissue. Our data provide evidence for the significance of PAK1 signaling as an element in the preservation of cardiac function and adipose tissue homeostasis in females during aging.
| S-EPMC7925422 | biostudies-literature