Astrid Rodríguez-Vélez

Washington University in St. Louis

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Babak Razani

Washington University in St. Louis

Se‐Jin Jeong

Washington University in St. Louis

Yu‐Sheng Yeh

University of Pittsburgh

Jeremiah Stitham

Washington University in St. Louis

Trent D. Evans

Washington University in St. Louis

Irfan J. Lodhi

Washington University in St. Louis

Xiangyu Zhang

China Agricultural University

Slava Epelman

University Health Network

Abhinav Diwan

Washington University in St. Louis

Joel D. Schilling

Washington University in St. Louis

Cooperative Institutions

Washington University in St. Louis

Cardiovascular Research Center

University of Pittsburgh

John Cochran VA Medical Center

University of Pittsburgh Medical Center

University of Missouri

Kyoto University

University of Illinois Chicago

University of Illinois Urbana-Champaign

University of Michigan–Ann Arbor

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p62/SQSTM1and Selective Autophagy in Cardiometabolic Diseases

Antioxidants and Redox Signaling (2018)

Se‐Jin Jeong Xiangyu Zhang Astrid Rodríguez-Vélez Trent D. Evans Babak Razani

Significance: p62/SQSTM1 is a multifunctional scaffolding protein involved in the regulation of various signaling pathways as well as autophagy. In particular, p62/SQSTM1 serves as an essential adaptor to identify and deliver specific organelles and protein aggregates to autophagosomes for degradation, a process known as selective autophagy. Critical Issues: With the emergence of autophagy as a critical process in cellular metabolism and the development of cardiometabolic diseases, it is increasingly important to understand p62's role in the integration of signaling and autophagic pathways. Recent Advances: This review first discusses the features that make p62/SQSTM1 an ideal chaperone in integrating signaling pathways with autophagy and details the current understanding of its diverse roles in selective autophagy processes. Distinct and overlapping roles of other chaperones with similar functions are then discussed in the context of p62/SQSTM1. Finally, the recent literature focusing on p62 and selective autophagy in metabolism and the spectrum of cardiometabolic diseases including atherosclerosis, fatty liver disease, and obesity is evaluated. Future Directions: A comprehensive understanding of the nuanced roles p62/SQSTM1 plays in mediating distinct autophagy pathways would provide new insights into the mechanisms of this critical degradative pathway. This will, in turn, facilitate our understanding of cardiovascular and cardiometabolic disease pathology and the development of novel autophagy-modulating therapeutic strategies.

ULK1

10.1089/ars.2018.7649

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Citations (111)

Autophagy Signaling and Oxidative Stress in Thoracic Aortic Aneurysms

JACC Basic to Translational Science (2021)

Arick C. Park Yu‐Sheng Yeh Astrid Rodríguez-Vélez Xiangyu Zhang Babak Razani

Thoracic aortic aneurysm

Aortic repair

10.1016/j.jacbts.2021.09.001

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Citations (1)

Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response

Figshare (2021)

Se‐Jin Jeong Jeremiah Stitham Trent D. Evans Xiangyu Zhang Astrid Rodríguez-Vélez

The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system. Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase

TFEB

Proteostasis

10.6084/m9.figshare.14206586.v1

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High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy

Nature Metabolism (2020)

Xiangyu Zhang Ismail Sergin Trent D. Evans Se‐Jin Jeong Astrid Rodríguez-Vélez

10.1038/s42255-019-0162-4

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Citations (122)

Abstract 551: Divergent Roles of Macrophage mTORC1 and mTORC2 Signaling in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology (2019)

Xiangyu Zhang Sunny Chen Astrid Rodríguez-Vélez Trent D. Evans Babak Razani

The mechanistic target of rapamycin (mTOR) pathway is considered as a key regulator of cellular proliferation, survival, metabolism, and degradation. Yet its role in atherosclerosis and in macropha...

mTORC2

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Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response

Autophagy (2021)

Se‐Jin Jeong Jeremiah Stitham Trent D. Evans Xiangyu Zhang Astrid Rodríguez-Vélez

The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase

TFEB

ATG16L1

Autophagosome

BAG3

Proteostasis

10.1080/15548627.2021.1896906

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Citations (79)

Abstract P147: Dietary Protein Elicits A Leucine-mediated Threshold Effect On Monocyte/macrophage Mtorc1-autophagy Signaling Resulting In Elevated Cardiovascular Risk

Arteriosclerosis Thrombosis and Vascular Biology (2021)

Xiangyu Zhang Divya Kapoor Se‐Jin Jeong Jeremiah Stitham Alan Fappi

High-protein intake is common in Western societies and generally considered healthy. However, results from some epidemiological studies suggest elevated protein intake is associated with increased risk for ischemic cardiovascular diseases. In addition, results from studies conducted in mice show that a high protein, compared with a standard Western diet, increases atherosclerosis burden and lesion complexity. The adverse effect of protein ingestion on plaque biology in mice is mediated by amino acid-mammalian target of rapamycin (mTOR)-dependent inhibition of autophagy in macrophages. Here, we evaluate the effect of graded amounts of protein ingestion on this amino acid-mTORC1-autophagy mechanism in human monocytes/macrophages and identify leucine as the key amino acid responsible for activating mTORC1 in macrophages. We describe the presence of a threshold effect of high protein intake on this deleterious signaling pathway wherein protein content greater than about 22% of total energy, which is consumed by nearly 1/4 th of the population in Western societies, acutely activates mTORC1 signaling in monocytes/macrophages. Furthermore, we identify leucine as the critical amino acid modulator and threshold indicator, capable of the dose-dependent mTORC1 activation and downstream functional effects. Finally, by designing specific mouse diets with protein contents mimicking graded levels of protein ingestion in our study participants, we demonstrate the presence of a dietary protein threshold effect in driving atherosclerosis in mouse models. These data demonstrate the potential deleterious impact of excessive protein intake on macrophages and atherosclerotic plaque progression.

Monocyte

10.1161/atvb.41.suppl_1.p147

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Abstract 433: Investigation Of The Divergent Roles Of Macrophage Mtor Signaling In Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology (2022)

Xiangyu Zhang Trent D. Evans Sunny Chen Ismail Sergin Se‐Jin Jeong

The mechanistic target of rapamycin (mTOR) pathway is considered a key regulator of cellular proliferation, survival, metabolism, and degradation. Yet its role in atherosclerosis and in macrophages of the atherosclerotic plaque remains poorly understood. Our previous study has demonstrated macrophage mTORC1 signaling promotes atherogenesis through inhibiting autophagy and increasing apoptosis. Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. In contrast to the protective effect against atherosclerosis from blocking macrophage mTORC1, macrophage-specific mTORC2-deficient mice have the opposite phenotype with the development of larger and more complex lesions. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 transcription factor leading to suppression of pro-inflammatory pathways, especially the inflammasome/IL-1β response, which also manifest in vivo. In addition, administration of FoxO1 inhibitors efficiently rescued the hyperinflammation caused by mTORC2 deficiency in vitro and in vivo. Interestingly, deletion of macrophage mTOR, which ablates both mTOR-dependent pathways leads to minimal change in plaques reflecting the apparently balanced and opposing roles of its signaling arms. Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.

mTORC2

FOXO1

10.1161/atvb.42.suppl_1.433

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Evaluation of mTORC1 signaling in mouse atherosclerotic macrophages by flow cytometry and immunofluorescence

STAR Protocols (2022)

Xiangyu Zhang Jeremiah Stitham Astrid Rodríguez-Vélez Se‐Jin Jeong Arick C. Park

Previous studies have demonstrated that a high-protein diet leads to increased atherosclerosis in mice, and that this adverse effect is caused by activation of macrophage mTORC1 signaling. Here, we provide a detailed protocol for the evaluation of diet-induced mTORC1 signaling in plaque macrophages in atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice. This protocol includes flow cytometry and immunofluorescence analysis of atherosclerotic macrophages that can be used to study the atherogenic potential of a variety of mTORC1 modulators. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2020).

Immunofluorescence

Knockout mouse

Apolipoprotein E

10.1016/j.xpro.2022.101665

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Inflammasomes: a preclinical assessment of targeting in atherosclerosis

Expert Opinion on Therapeutic Targets (2020)

Jeremiah Stitham Astrid Rodríguez-Vélez Xiangyu Zhang Se‐Jin Jeong Babak Razani

Introduction Inflammasomes are central to atherosclerotic vascular dysfunction with regulatory effects on inflammation, immune modulation, and lipid metabolism. The NLRP3 inflammasome is a critical catalyst for atherogenesis thus highlighting its importance in understanding the pathophysiology of atherosclerosis and for the identification of novel therapeutic targets and biomarkers for the treatment of cardiovascular disease.Areas covered This review includes an overview of macrophage lipid metabolism and the role of NLRP3 inflammasome activity in cardiovascular inflammation and atherosclerosis. We highlight key activators, signal transducers and major regulatory components that are being considered as putative therapeutic targets for inhibition of NLRP3-mediated cardiovascular inflammation and atherosclerosis.Expert opinion NLRP3 inflammasome activity lies at the nexus between inflammation and cholesterol metabolism; it offers unique opportunities for understanding atherosclerotic pathophysiology and identifying novel modes of treatment. As such, a host of NLRP3 signaling cascade components have been identified as putative targets for drug development. We catalog these current discoveries in therapeutic targeting of the NLRP3 inflammasome and, utilizing the CANTOS trial as the translational (bench-to-bedside) archetype, we examine the complexities, challenges, and ultimate goals facing the field of atherosclerosis research.

10.1080/14728222.2020.1795831

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Citations (11)