Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction

Sciarretta, Sebastiano; Yee, Derek; Nagarajan, Narayani; Bianchi, Franca; Saito, Toshiro; Valenti, Valentina; Tong, Mingming; Re, Dominic P. Del; Vecchione, Carmine; Schirone, Leonardo; Forte, Maurizio; Rubattu, Speranza; Shirakabe, Akihiro; Boppana, V. Subbarao; Volpe, Massimo; Frati, Giacomo; Zhai, Peiyong; Sadoshima, Junichi

doi:10.1016/j.jacc.2018.02.066

Cited by 213 publications

(160 citation statements)

References 42 publications

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“…Some mice were administered trehalose (1 g/kg, MP Biochemicals, Solon, OH, USA) intraperitoneally at the time point of 48, 24, and 2 h before starting MV. Trehalose dose was chosen based on a previously published studies (40,41).…”

Section: Fasting and Trehalose Treatmentmentioning

confidence: 99%

“…We next hypothesized that use of another known autophagy inducer would also decrease the production of IL-1β by AMs and therefore provide a potential protection against hypoxemia in this experimental ALI model. Trehalose, a naturally occurring disaccharide, has been proposed as an mTOR-independent autophagy enhancer (47) and was reported to have therapeutic effects against atherosclerosis, myocardial infarction, spinal cord injury, traumatic brain injury, and Alzheimer's disease (40,(48)(49)(50)(51). Therefore, we investigated the therapeutic effect of this mTOR-independent autophagy activator in our two-hit ALI mouse model.…”

Section: Trehalose An Mtor-independent Autophagy Enhancer Does Not mentioning

confidence: 99%

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Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

et al. 2020

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Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmH 2 O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1 fl/fl LysM Cre ) suffered severe hypoxemia (adjusted p < 0.05) and increased lung permeability (p < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space (p < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted p < 0.0001) and lung permeability (p < 0.05), as well as significantly suppressed IL-1β production (p < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted p < 0.01) as well as lung permeability (p < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.

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Section: Fasting and Trehalose Treatmentmentioning

confidence: 99%

Section: Trehalose An Mtor-independent Autophagy Enhancer Does Not mentioning

confidence: 99%

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

et al. 2020

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“…For a detailed discussion, consult main text the exception of the (controversial) maladaptive autophagy occurring during pressure overload [17], it appears that autophagy induction reduces myocardial damage after acute insult by ischemia. Preclinical evidence suggests that a variety of autophagy inducers including trehalose can improve the outcome of myocardial infarction [72]. Of note, coronary stents releasing rapamycin are FDA/EMA approved because of their superior clinical efficacy [73].…”

Section: Cardiovascular Diseasementioning

confidence: 99%

Therapeutic modulation of autophagy: which disease comes first?

Maiuri

Kroemer

2019

Cell Death Differ

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The relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy "druggable". Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation. Facts • Autophagy is one of the best-studied phenomena in cell biology. Drugs for enhancing or inhibiting general or specific autophagy are being developed. • Acquired or genetically determined alterations in autophagic flux are involved in multiple pathologies across the entire spectrum of human diseases. • Autophagy inhibition might be useful for the avoidance of unwarranted autophagy-dependent cell death. • Chronic autophagy stimulation has a positive impact on preclinical models of aging and multiple distinct agedependent diseases, including arteriosclerosis, cancer, and neurodegeneration. Acute autophagy stimulation also has organ-protective effects in models of ischemia or intoxication.

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“…Indeed, administration of trehalose, a safe non-reducing sugar has been demonstrated to be effective in activating TFEB in macrophages (185) and cardiac myocytes (181); and trehalose treatment attenuated atherosclerosis as well as post-myocardial infarction remodeling in an autophagy-dependent fashion raising hopes for developing lysosome-targeted therapies for cardiovascular disease.…”

Section: Lysosomes As Regulators Of Cardiac Homeostasis and The Fastimentioning

confidence: 99%

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

Mani

Javaheri

Diwan

2018

Comprehensive Physiology

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Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.

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Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction

Abstract: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.

Cited by 213 publications

References 42 publications

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

Therapeutic modulation of autophagy: which disease comes first?

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

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