Mitochondrial Metabolism in Myocardial Remodeling and Mechanical Unloading: Implications for Ischemic Heart Disease

Jiang, Min; Xie, Xiaoye; Cao, Feng; Wang, Yabin

doi:10.3389/fcvm.2021.789267

Cited by 28 publications

(22 citation statements)

References 175 publications

(207 reference statements)

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“…Thus, inhibition of glycolysis can inhibit the activation of fibroblasts and improve organ fibrosis [ 55 – 58 ]. This change of energy metabolism may be an adaptive measure under hypoxia, as cells tend to undergo glycolysis in the absence of oxygen [ 59 , 60 ]. Thus, we speculate that restoring normal levels of fatty acid metabolism may be a potential treatment for fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Gpx3 and Egr1 Are Involved in Regulating the Differentiation Fate of Cardiac Fibroblasts under Pressure Overload

Qin

Cheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objectives. Although myocardial fibrosis is a common pathophysiological process associated with many heart diseases, the molecular mechanisms regulating the development of fibrosis have not been fully determined. Recently, single cell RNA sequencing (scRNA-seq) analysis has been used to examine cellular fate and function during cellular differentiation and has contributed to elucidating the mechanisms of various diseases. The main purpose of this study was to characterize the fate of cardiac fibroblasts (CFs) and the dynamic gene expression patterns in a model of cardiac pressure overload using scRNA-seq analysis. Methods. The public scRNA-seq dataset of the transverse aortic coarctation (TAC) model in mice was downloaded from the GEO database, GSE155882. First, we performed quality control, dimensionality reduction, clustering, and annotation of the data through the Seurat R package (v4.0.5). Then, we constructed the pseudotime trajectory of cell development and identified key regulatory genes using the Monocle R package (v2.22.0). Different cell fates and groups were fully characterized by Gene Set Enrichment Analysis (GSEA) analysis and Transcription factor (TF) activity analysis. Finally, we used Cytoscape (3.9.1) to extensively examine the gene regulatory network related to cell fate. Results. Pseudotime analysis showed that CFs differentiated into two distinct cell fates, one of which produced activated myofibroblasts, and the other which produced protective cells that were associated with reduced fibrosis levels, increased antioxidative stress responses, and the ability to promote angiogenesis. In the TAC model, activated CFs were significantly upregulated, while protective cells were downregulated. Treatment with the bromodomain inhibitor JQ1 reversed this change and improved fibrosis. Analysis of dynamic gene expression revealed that Gpx3 was significantly upregulated during cell differentiation into protective cells. Gpx3 expression was affected by JQ1 treatment. Furthermore, Gpx3 expression levels were negatively correlated with the different levels of fibrosis observed in the various treatment groups. Finally, we found that transcription factors Jun, Fos, Atf3, and Egr1 were upregulated in protective cells, especially Egr1 was predicted to be involved in the regulation of genes related to antioxidant stress and angiogenesis, suggesting a role in promoting differentiation into this cell phenotype. Conclusions. The scRNA-seq analysis was used to characterize the dynamic changes associated with fibroblast differentiation and identified Gpx3 as a factor that might be involved in the regulation of myocardial fibrosis under cardiac pressure overload. These findings will help to further understanding of the mechanism of fibrosis and provide potential intervention targets.

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Section: Discussionmentioning

confidence: 99%

Gpx3 and Egr1 Are Involved in Regulating the Differentiation Fate of Cardiac Fibroblasts under Pressure Overload

Qin

Cheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…As a consequence of energy depletion, anaerobic glycolysis is triggered, and lactate is produced. Although initially lactate is utilized for the production of ATP, albeit with less metabolic efficiency, with prolonged ischemia it accumulates in the cells, decreasing the intracellular pH, which will further inhibit the glycolytic enzymes and lead to further energy depletion, calcium cellular overload and finally to altered cellular function and death [ 27 , 28 ].…”

Section: Pathophysiology Of Adverse Remodelingmentioning

confidence: 99%

“…The result is cardiac myocyte hypercontracture and death. Furthermore, ROS act as chemoattractants for neutrophils, which further contribute to the local inflammation and damage [ 22 , 27 , 28 ].…”

Section: Pathophysiology Of Adverse Remodelingmentioning

confidence: 99%

“…Although free fatty acids are normally the main source of ATP, the hibernating tissue manifests a shift towards glucose substrate, as a protective mechanism to enable anaerobic metabolism during ischemic episodes. Although in “hibernating myocardium” dysfunction is reversible after reperfusion, it can progress to irreversible cellular damage and myocardium necrosis in the case of prolonged, severe ischemia and in the absence of reperfusion, finally leading to adverse ventricular remodeling [ 27 , 28 ].…”

Section: Pathophysiology Of Adverse Remodelingmentioning

confidence: 99%

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Left Ventricular Remodeling after Myocardial Infarction: From Physiopathology to Treatment

Leancă

Crișu

Petriş

et al. 2022

Life

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Myocardial infarction (MI) is the leading cause of death and morbidity worldwide, with an incidence relatively high in developed countries and rapidly growing in developing countries. The most common cause of MI is the rupture of an atherosclerotic plaque with subsequent thrombotic occlusion in the coronary circulation. This causes cardiomyocyte death and myocardial necrosis, with subsequent inflammation and fibrosis. Current therapies aim to restore coronary flow by thrombus dissolution with pharmaceutical treatment and/or intravascular stent implantation and to counteract neurohormonal activation. Despite these therapies, the injury caused by myocardial ischemia leads to left ventricular remodeling; this process involves changes in cardiac geometry, dimension and function and eventually progression to heart failure (HF). This review describes the pathophysiological mechanism that leads to cardiac remodeling and the therapeutic strategies with a role in slowing the progression of remodeling and improving cardiac structure and function.

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“…In CAD, myocardial ischemia is the primary indication for PCI and also a prominent factor in myocardial remodeling (6,7). On the other hand, myocardial remodeling aggravates myocardial ischemia (8). Therefore, there is a mutual increase in myocardial ischemia and myocardial remodeling, which may aid in quantifying the myocardial blood flow (9).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Advantages of Myocardial Blood Flow Index in the Diagnosis of Chronic Obstructive Coronary Artery Disease Versus Coronary Computed Tomography Angiography: A Feasibility Study

Qingfeng

et al. 2022

Iran J Radiol

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Background: There is a hidden relationship between the degree of coronary artery stenosis and downstream myocardial remodeling. The mutual influence in myocardial ischemia and myocardial remodeling provides an index for quantifying the myocardial blood flow based on the principles of physics. Objectives: This study aimed to evaluate the advantages of myocardial blood flow index (MBFI) in the diagnosis of chronic obstructive coronary artery disease (CAD). Patients and Methods: The data of 68 patients (39 males; mean age: 57.0 ± 10.20 years) with suspected CAD were analyzed retrospectively, including the imaging findings of coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) within one week. The MBFI was also calculated for the patients. After determining the optimal cut-off value based on ICA (stenosis ≥ 70%) as the gold standard test, the diagnostic performance of MBFI and CCTA was compared. The diagnostic accuracy was examined by the receiver operating characteristic (ROC) curve. For statistical analysis, chi-square test was performed to analyze influence data, and a P-value less than 0.05 was considered statistically significant. Results: In 68 cases evaluated in this study, the average scan dose of CCTA was 3.02 ± 1.15 mSv. There were 28 cases with stenosis ≥ 70%. The optimal cutoff value of MBFI and CCTA was 0.111 and 70%, respectively. Also, the area under the curve (AUC) for MBFI and CCTA was 0.857 and 0.621 (Z = 2.091, P = 0.0365), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 92.31%, 92.86%, 88.89%, and 95.12% for MBFI and 61.54%, 78.57%, 64.00%, and 76.74% for CCTA, respectively. The diagnostic accuracy was also estimated at 92.65% for MBFI and 72.06% for CCTA (χ2 = 9.844, P = 0.0017). Conclusion: In this study, MBFI performed better than CCTA in identifying lesions with stenosis ≥ 70%. A lower MBFI indicated the need for an upcoming active intervention, while a higher MBFI suggested avoiding unnecessary invasive testing.

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Mitochondrial Metabolism in Myocardial Remodeling and Mechanical Unloading: Implications for Ischemic Heart Disease

Cited by 28 publications

References 175 publications

Gpx3 and Egr1 Are Involved in Regulating the Differentiation Fate of Cardiac Fibroblasts under Pressure Overload

Gpx3 and Egr1 Are Involved in Regulating the Differentiation Fate of Cardiac Fibroblasts under Pressure Overload

Left Ventricular Remodeling after Myocardial Infarction: From Physiopathology to Treatment

Evaluation of the Advantages of Myocardial Blood Flow Index in the Diagnosis of Chronic Obstructive Coronary Artery Disease Versus Coronary Computed Tomography Angiography: A Feasibility Study

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