Cigarette smoke increases cardiomyocyte ceramide accumulation and inhibits mitochondrial respiration

Tippetts, Trevor S.; Winden, Duane R.; Swensen, Adam; Nelson, Michael B.; Thatcher, Mikayla O.; Saito, Rex R.; Condie, Tyler B; Simmons, Kurtis; Judd, Allan M.; Reynolds, Paul; Bikman, Benjamin T.

doi:10.1186/1471-2261-14-165

Cited by 32 publications

(36 citation statements)

References 33 publications

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“…As previously reported in CS-exposed mice fed regular chow [18], mice displayed reduced total body weight gain during CS exposure, even when fed HFD. This observation is consistent with known effects of CS to suppress appetite and increase energy expenditure [20]. Glucose and insulin tolerance largely followed weight patterns, and mice exposed to CS were more glucose tolerant and more insulin sensitive compared to HFD-fed non-exposed mice.…”

Section: Discussionsupporting

confidence: 88%

“…Exposure to CSE, derived from smoke condensate followed by removal of particulate matter, has been extensively used in ex vivo models [14][15][16][17][18]. Previous studies have reported a significant increase in ceramide in the lung and other tissues after experimental exposure to CS [18][19][20], so we also tested whether CS-exposure influenced β -cell ceramide content.…”

mentioning

confidence: 99%

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Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

Tong

Chaudhry

Lee

et al. 2019

Preprint

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ObjectivesEpidemiological studies indicate that first- and second-hand cigarette smoke (CS) exposure are important risk factors for the development of type 2 diabetes (T2D). Additionally, elevated diabetes risk has been reported to occur within a short period of time after smoking cessation, and health risks associated with smoking are increased when combined with obesity. At present, the mechanisms underlying these associations remain incompletely understood. The objective of this study was to test the impact of CS exposure on pancreatic β-cell function using rodent and in vitro models.MethodsBeginning at 8 weeks of age, C57BL/6J mice were concurrently fed high fat-diet (HFD) and exposed to CS for 11 weeks, followed by an additional 11 weeks of smoking cessation with continued HFD exposure. Glucose tolerance testing was performed during CS exposure and during the cessation period. Cultured β-cells (INS-1) and primary islets were exposed ex vivo to CS extract (CSE), and β-cell function and viability were tested. Since CS increases ceramide in lungs cells and these bioactive sphingolipids have been implicated in pancreatic β-cell dysfunction in diabetes, islet and β-cell sphingolipid levels were measured in islets from CS-exposed mice and in CSE-treated islets and INS-1 cells using liquid chromatography-tandem mass spectrometry.ResultsCompared to HFD-fed ambient air-exposed mice, HFD-fed and CS- exposed mice had reduced weight gain and better glucose tolerance during the active smoking period. Following smoking cessation, CS-mice exhibited rapid weight gain and a significantly greater increase in glucose intolerance compared to non-smoking control mice. CS-exposed mice had higher serum proinsulin/insulin ratios, indicative of β-cell dysfunction, significantly lower β-cell mass (p=0.02), and reduced β-cell proliferation (p=0.006), and increased islet ceramide accumulation. Ex vivo exposure of isolated islets to CSE was sufficient to increase islet ceramide accumulation, reduce insulin gene expression and glucose-stimulated insulin secretion, and increase β-cell oxidative and ER stress. Treatment with the antioxidant N-acetylcysteine, markedly attenuated the effects of CSE on ceramide levels, restored β-cell function and survival, and increased cyclin D2 expression, while also reducing activation of β-cell ER and oxidative stress.ConclusionsOur results indicate that CS exposure inhibits insulin production, processing, and secretion and reduced β-cell viability and proliferation. These effects were linked to increased β-cell oxidative and ER stress and ceramide accumulation. Mice fed HFD continued to experience detrimental effects of CS exposure even during smoking cessation. Elucidation of mechanisms by which CS exposure impairs β-cell function in synergy with obesity will help design therapeutic and preventive interventions for both active and former smokers.

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

Tong

Chaudhry

Lee

et al. 2019

Preprint

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“…Cells were prepared for mitochondrial respiration as described previously 27,28 before being transferred to respirometer chambers using the Oroboros O2K oxygraph. Electron flow through complex I was supported by glutamate + malate (10 mM and 2 mM, respectively) to determine leak oxygen consumption (GM L ).…”

Section: Mitochondrial Respirationmentioning

confidence: 99%

β-Hydroxybutyrate improves β-cell mitochondrial function and survival

Sampson

Lathen

Dallon

et al. 2017

JMH

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Pharmacological interventions aimed at improving outcomes in type 2 diabetes and achieving normoglycaemia, including insulin therapy, are increasingly common, despite the potential for substantial side effects. Carbohydrate-restricted diets that result in increased ketogenesis have effectively been used to improve insulin resistance, a fundamental feature of type 2 diabetes. In addition, limited evidence suggests that states of ketogenesis may also improve β-cell function in type 2 diabetics. Considering how little is known regarding the effects of ketones on β-cell function, we sought to determine the specific effects of β-Hydroxybutyrate (βHB) on pancreatic β-cell physiology and mitochondrial function. βHB treatment increased β-cell survival and proliferation, while also increasing mitochondrial mass, respiration and adenosine triphosphate (ATP) production. Despite these improvements, were unable to detect an increase in β-cell or islet insulin production and secretion. Collectively, these findings have two implications. Firstly, they indicate that β-cells have improved survival and proliferation in the midst of βHB, the circulating form of ketones. Secondly, insulin secretion does not appear to be directly related to apparent improvements in mitochondrial function and cellular proliferation.

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“…In particular, cigarette smoke pathologically alters sphingolipid metabolism, resulting in the accrual of ceramides, the backbone of higher-order sphingolipids, in heart [162] and skeletal muscle [178]—two key insulin-responsive tissues. Ceramide accrual in these tissues resulted in substantial disruption of mitochondrial function, including alterations in morphology and electron transport.…”

Section: Health Outcomes and Comorbiditiesmentioning

confidence: 99%

“…Research has even demonstrated that, after only 20 min of SHS exposure, direct endothelial cell injury is observed. Mechanistically, SHS exposure has been shown to increase free radicals [187] while decreasing antioxidants [188], decrease mitochondrial function [178], decrease protective HDL levels [189,190], and increase arterial stiffness [191]. Such staggering data adds new meaning to the current warnings from the Surgeon General that state “there is no safe level of exposure to tobacco smoke” [114].…”

Section: Health Outcomes and Comorbiditiesmentioning

confidence: 99%

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

Lewis

Hirschi

Arroyo

et al. 2017

IJMS

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Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First-and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed.

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Cigarette smoke increases cardiomyocyte ceramide accumulation and inhibits mitochondrial respiration

Cited by 32 publications

References 33 publications

Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

Cigarette Smoke Exposure Impairs β-Cell Function Through Activation of Oxidative Stress and Ceramide Accumulation

β-Hydroxybutyrate improves β-cell mitochondrial function and survival

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

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