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TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy.

ABSTRACT: Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1? secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (M?-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1? compared with controls. Surprisingly, neither inflammasome suppression nor M?-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that M?-TFEB upregulated key targets involved in lysosomal lipid metabolism. Specifically, inhibition of the TFEB target, lysosomal acid lipase, in vivo abrogated the beneficial effect of M?-TFEB on postinfarction ventricular function. Thus, TFEB reprograms macrophage lysosomal lipid metabolism to attenuate remodeling after IR, suggesting an alternative paradigm whereby lysosome function affects inflammation.

SUBMITTER: Javaheri A

PROVIDER: S-EPMC6948771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:There is heated debate about the benefits of using mineralocorticoid receptor antagonists (MRAs) in addition to standard therapy in patients admitted for myocardial infarction (MI) with or without left ventricular dysfunction (LVD). METHODS:Randomized controlled trials (RCTs) were scanned by a formal search of electronic databases (PubMed, EMBASE, Cochrane Library, Ovid, and clinical trials) from their inception to April 2018. A meta-analysis was conducted using Review Manager 5.3 to identify studies reporting the efficacy of MRAs use in post-MI patients with or without LVD. RESULTS:Thirteen RCTs involving 11,365 individuals were eligible for this study. MRAs treatment reduced all-cause mortality by 16%, cardiovascular death by 16%, and death from heart failure (HF) by 22% in post-MI patients. MRAs use reduced all-cause mortality by 13% and cardiovascular death by 15% in post-MI patients with LVD, but there was no significant difference in all-cause mortality and cardiovascular death in post-MI patients without LVD (relative ratios [RR] 0.83, 95% confidence interval [CI] 0.26-2.69, P = .76, I = 0%; RR 1.01, 95% CI 0.33-3.09, P = .99, I = 0%). In 6 RCTs involving post-MI patients, MRAs treatment had a significant effect on improving left ventricular ejection fraction (LVEF) (mean difference 3.33, 95% CI 0.91-5.75, P = .007, I = 94%). Patients treated with MRAs did not show a decrease in recurrent MI or repeat revascularization compared with patients treated without MRAs (RR 0.95, 95% CI [0.80-1.12], P = .54, I = 0%; RR 1.09, 95% CI [0.79-1.50], P = .61, I = 0%). However, MRAs treatment significantly increased the incidence of hyperkalemia compared with patients treated without MRAs (RR 2.05, 95% CI [1.60, 2.61], P < .00001, I = 49%). CONCLUSION:MRAs treatment reduced all-cause mortality, cardiovascular death, and death from HF in post-MI patients. MRAs treatment also demonstrated a significant improvement in LVEF. MRAs reduced cardiovascular death and all-cause mortality in patients with LVD. Eplerenone significantly reduced all-cause mortality and cardiovascular death in post-MI patients. However, MRAs failed to show any cardiovascular benefit in post-MI patients without LVD.

Project description:BACKGROUND: A significant proportion of myocardial infarction (MI) patients undergo complex, coordinated perturbations at the molecular level that may eventually drive the occurrence of ventricular dysfunction and heart failure. Despite advances in the elucidation of key processes implicated in this condition, traditional methods relying on gene expression data and the identification of individual biomarkers in isolation pose major limitations not only for improving prediction power, but also for model interpretability. Mechanisms underlying clinical responses after MI remain elusive and there is no biomarker with the capacity to accurately predict ventricular dysfunction after MI. This calls for the exploration of system-level modeling of ventricular dysfunction in post-MI patients. Within this discovery framework key perturbations and predictive patterns are characterized by the integrated biological activity levels observed in pathways, rather than in individual genes. METHODOLOGY/PRINCIPAL FINDINGS: Here we report an integrative approach to identifying pathways related with ventricular dysfunction post MI with potential prognostic and therapeutic value. We found that a diversity of pathway-level perturbations can be profiled in samples of patients with ventricular dysfunction post MI, most of which represent major reductions of gene expression. Highly perturbed pathways included those implicated in antigen-dependent B-cell activation and the synthesis of leucine. By analyzing patient-specific samples encoded with information derived from highly-perturbed pathways, it is possible to visualize differential prognostic patterns and to perform computational classification of patients with areas under the receiver operating characteristic curve above 0.75. We also demonstrate how the integration of the outcomes generated by different pathway-based analysis models may improve ventricular dysfunction prediction performance. SIGNIFICANCE: This research offers an alternative, comprehensive view of key relationships and perturbations that may trigger the emergence or prevention of ventricular dysfunction post-MI.

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TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy.

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