Abstract 18666: Macrophage TFEB Overexpression Attenuates Left Ventricular Remodeling After Myocardial Infarction

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Abstract

Introduction: Post-myocardial infarction (MI), myocardial macrophage expansion via proliferation of resident cells and recruitment of circulating monocytes modulates healing via phagocytosis of dead cells and is also implicated in pro-inflammatory signaling that provokes heart failure. Whether the macrophage autophagy-lysosome pathway can be harnessed to prevent heart failure remains unknown.

Hypothesis: Augmentation of the autophagy-lysosome machinery by overexpression of transcription factor EB (TFEB), a master regulator of this pathway, ameliorates post-MI left ventricular (LV) remodeling after ischemia-reperfusion (IR) injury.

Methods: Adult mice carrying Cx3Cr1-er-Cre and TFEB lox-STOP cassette were treated with tamoxifen to inducibly overexpress TFEB in recruited and/or resident macrophages after closed-chest IR injury and assessed by echocardiography.

Results: At 4 weeks post-MI, Cre-only controls demonstrated adverse LV remodeling with significant increases in end-diastolic volume (EDV, by 72% vs. pre-ischemia) and decreased ejection fraction (EF, 26.5 ± 3.6% vs. 61.4 ± 4.0% pre-ischemia, p<0.001). Inducible TFEB overexpression in both resident and recruited macrophages did not affect baseline LV structure and function, but attenuated post-MI remodeling (EDV increased by 12% and post-MI EF was 46.9 ± 4.4%, p=0.013 and <0.01 vs. Cre-only controls, respectively). The area-at-risk and scar size were similar, indicating that the observations were not due to different infarct sizes. TFEB overexpression did not alter the composition of inflammatory cells, post-MI, but resulted in a strong trend towards reduced TUNEL+ cardiomyocytes in the remote myocardium. TFEB overexpression restricted to resident macrophages did not attenuate post-IR remodeling, suggesting a critical role for augmented lysosome function in recruited cells. Furthermore, macrophage TFEB overexpression failed to attenuate remodeling when autophagy was genetically perturbed via macrophage deletion of Atg5.

Conclusion: Macrophage TFEB activation attenuates post-IR adverse ventricular remodeling via entraining the autophagy pathway in recruited macrophages.

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