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

Javaheri, Ali; Bajpai, Geetika; Picataggi, Antonino; Mani, Smrithi; Foroughi, Layla; Evie, Hosannah; Kovács, Attila; Weinheimer, Carla J.; Hyrc, Krzystztof; Xiao, Qingli; Ballabio, Andrea; J, Lee; Matkovich, Scot J.; Razani, Babak; Schilling, Joel D.; Lavine, Kory J.; Diwan, Abhinav

doi:10.1172/jci.insight.127312

Cited by 44 publications

(31 citation statements)

References 64 publications

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“…Failure of the ubiquitin-proteasome system and autophagy-lysosome pathways has also been implicated in more common forms of cardiomyopathy and heart failure resulting from ischemiareperfusion injury and pressure overload stress (reviewed in Wang et al, 2011). Specifically, we have uncovered evidence for lysosome impairment in cardiac myocytes (Ma et al, 2012a,b) and macrophages (Javaheri et al, 2019) in the setting of myocardial ischemia-reperfusion injury, at least in part due to suppression of the lysosome biogenesis program (Godar et al, 2015;Ma et al, 2015). This impairment of autophagylysosome pathway is associated with accumulation of polyubiquitinated proteins (Godar et al, 2015), pointing to a critical role for this pathway in protein quality control in the setting of ischemia-reperfusion injury.…”

Section: Proteostatic Failure In Heart Disease: the Devil In The Heartmentioning

confidence: 98%

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

2020

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Homeostasis in vertebrate systems is contingent on normal cardiac function. This, in turn, depends on intricate protein-based cellular machinery, both for contractile function, as well as, durability of cardiac myocytes. The cardiac small heat shock protein (csHsp) chaperone system, highlighted by αB-crystallin (CRYAB), a small heat shock protein (sHsp) that forms ∼3-5% of total cardiac mass, plays critical roles in maintaining proteostatic function via formation of self-assembled multimeric chaperones. In this work, we review these ancient proteins, from the evolutionarily preserved role of homologs in protists, fungi and invertebrate systems, as well as, the role of sHsps and chaperones in maintaining cardiac myocyte structure and function. We propose the concept of the "sarcostat" as a protein quality control mechanism in the sarcomere. The roles of the proteasomal and lysosomal proteostatic network, as well as, the roles of the aggresome, self-assembling protein complexes and protein aggregation are discussed in the context of cardiac myocyte homeostasis. Finally, we will review the potential for targeting the csHsp system as a novel therapeutic approach to prevent and treat cardiomyopathy and heart failure.

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Section: Proteostatic Failure In Heart Disease: the Devil In The Heartmentioning

confidence: 98%

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

2020

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“…Macrophage-specific TFEB-overexpressing transgenic mice exhibit increased lysosome biogenesis and proteolytic capacity in macrophages with atherogenic lipids [257]. Furthermore, the lysosome-autophagy pathway is dysfunctional in mice with ischemia/reperfusion (IR) injury and in cardiac macrophages of humans with ischemic cardiomyopathy [258]. Transgenic mice with macrophage-specific TFEB overexpression demonstrate attenuated ventricular dysfunction and IL-1β secretion post IR injury, likely due to upregulation of lysosomal acid lipase [258].…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

Lysosomal Biology and Function: Modern View of Cellular Debris Bin

Trivedi

Bartlett

Pulinilkunnil

2020

Cells

200

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Lysosomes are the main proteolytic compartments of mammalian cells comprising of a battery of hydrolases. Lysosomes dispose and recycle extracellular or intracellular macromolecules by fusing with endosomes or autophagosomes through specific waste clearance processes such as chaperone-mediated autophagy or microautophagy. The proteolytic end product is transported out of lysosomes via transporters or vesicular membrane trafficking. Recent studies have demonstrated lysosomes as a signaling node which sense, adapt and respond to changes in substrate metabolism to maintain cellular function. Lysosomal dysfunction not only influence pathways mediating membrane trafficking that culminate in the lysosome but also govern metabolic and signaling processes regulating protein sorting and targeting. In this review, we describe the current knowledge of lysosome in influencing sorting and nutrient signaling. We further present a mechanistic overview of intra-lysosomal processes, along with extra-lysosomal processes, governing lysosomal fusion and fission, exocytosis, positioning and membrane contact site formation. This review compiles existing knowledge in the field of lysosomal biology by describing various lysosomal events necessary to maintain cellular homeostasis facilitating development of therapies maintaining lysosomal function.

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“…81,82 Along with this notion, inducible macrophage-specific overexpression of TFEB, a master regulator of autophagy, attenuated post-infarction remodeling and decreased the accumulation of pro-inflammatory macrophages, despite a lack of direct evidence linking the cardioprotection to autophagy. 83 Our and others' studies have demonstrated that impaired autophagy flux contributes to cardiac dysfunction and adverse remodeling after myocardial infarction (MI). 17,84 We found that the upregulation of DNA damage-regulated autophagy modulator 1 (DRAM1) protected against impaired autophagy flux and conferred myocardial protection against ischemia.…”

Section: Cardiac Ischemic Diseasementioning

confidence: 99%

“…In this regard, autophagy provides compensatory protection for cardiomyocytes against nutrient deficiency, while mitophagy alleviates the cardiotoxicity of dysfunctional mitochondria 81,82 . Along with this notion, inducible macrophage‐specific overexpression of TFEB, a master regulator of autophagy, attenuated post‐infarction remodeling and decreased the accumulation of pro‐inflammatory macrophages, despite a lack of direct evidence linking the cardioprotection to autophagy 83 . Our and others' studies have demonstrated that impaired autophagy flux contributes to cardiac dysfunction and adverse remodeling after myocardial infarction (MI) 17,84 .…”

Section: Autophagy Dysregulation and Cardiac Pathologiesmentioning

confidence: 99%

Autophagy and cardiac diseases: Therapeutic potential of natural products

Liu

et al. 2020

Medicinal Research Reviews

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The global incidence of cardiac diseases is expected to increase in the coming years, imposing a substantial socioeconomic burden on healthcare systems. Autophagy is a tightly regulated lysosomal degradation mechanism important for cell survival, homeostasis, and function. Accumulating pieces of evidence have indicated a major role of autophagy in the regulation of cardiac homeostasis and function. It is well established that dysregulation of autophagy in cardiomyocytes is involved in cardiac hypertrophy, myocardial infarction, diabetic cardiomyopathy, and heart failure. In this sense, autophagy seems to be an attractive therapeutic target for cardiac diseases. Recently, multiple natural products/phytochemicals, such as resveratrol, berberine, and curcumin have been shown to regulate cardiomyocyte autophagy via different pathways. The autophagy‐modifying capacity of these compounds should be taken into consideration for designing novel therapeutic agents. This review focuses on the role of autophagy in various cardiac diseases and the pharmacological basis and therapeutic potential of reported natural products in cardiac diseases by modifying autophagic processes.

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

Cited by 44 publications

References 64 publications

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

Lysosomal Biology and Function: Modern View of Cellular Debris Bin

Autophagy and cardiac diseases: Therapeutic potential of natural products

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