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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-1β 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 (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that Mϕ-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 Mϕ-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 | 2019 Nov

REPOSITORIES: biostudies-literature

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

Javaheri Ali A Bajpai Geetika G Picataggi Antonino A Mani Smrithi S Foroughi Layla L Evie Hosannah H Kovacs Attila A Weinheimer Carla J CJ Hyrc Krzystztof K Xiao Qingli Q Ballabio Andrea A Lee Jin-Moo JM Matkovich Scot J SJ Razani Babak B Schilling Joel D JD Lavine Kory J KJ Diwan Abhinav A

JCI insight 20191101 21

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β 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 ...[more]

PMID: 31672943

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Project description:BackgroundThere 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).MethodsRandomized 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.ResultsThirteen 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%).ConclusionMRAs 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.

Dataset Information

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

Publications

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

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