Enhanced Myocardial Glucose Delivery Accelerates Development of Mitochondrial Dysfunction in the Diabetic Heart
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ABSTRACT:
PROVIDER: PRJNA510408 | ENA |
REPOSITORIES: ENA
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Project description:Cardiac glucose delivery and utilization are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetic patients. The loss of mitochondrial substrate flexibility in regulating cellular and cardiac function is actively under investigation.
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Project description:Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.
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Project description:Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). In this study, we investigated the outcome of the delivery of hUCM-MSC after reperfusion in a translational model of AMI in swine. We have found that intracoronary injection of the cell product was associated with improved systolic function and that improvement in mechanical performance. This did not depend on the reduction of morphological infarct size alone, despite treated animals showing signs of less adverse remodeling.
2023-06-01 | E-MTAB-13022 | biostudies-arrayexpress
Project description:Myocardial Infarction accelerates breast cancer via innate immune reprogramming (ATAC-seq)
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Project description:Myocardial Infarction accelerates breast cancer via innate immune reprogramming (RNA-seq)
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Project description:Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
2020-06-11 | GSE135353 | GEO
Project description:Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
2020-06-11 | GSE137789 | GEO
Project description:Enhanced Myocardial Repair with CardioClusters
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Project description:Patients with non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), have an increased risk of cardiovascular diseases (CVD) due to the production of pro-inflammatory factors, vasoactive and thrombogenic molecules, or insulin resistance and related disorders. While elevated risk and incidence of CVD events in NAFLD/NASH are well established, whether such events will, in turn, influence the pathogenesis of NAFLD remains unknown. Here, we show that myocardial infarction (MI) accelerates the linear hepatic pathological progression of NAFLD. In humans, NAFLD patients who experienced CVD events after their diagnosis of NAFLD show a rapid progression of hepatic fibrosis. In mouse models of NASH, MI promotes hepatic fibrosis, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to the damaged liver tissues. Depleting these cells abrogate MI-induced hepatic pathological effects in mice with NASH. Meanwhile, MI substantially elevates circulating and cardiac periostin contents, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of NASH. Additionally, specific silence of cardiac periostin markedly attenuates MI-induced hepatic pathological progression of mice with NASH. These preclinical and clinical results demonstrate that MI alternates systemic homeostasis and upregulates the production of pro-fibrotic factors, triggering cross-disease communication that accelerates hepatic pathological progression of NAFLD.
2024-06-04 | GSE254698 | GEO