Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner

Nelson, Michael B.; Swensen, Adam; Winden, Duane R.; Bodine, Jared S; Bikman, Benjamin T.; Reynolds, Paul

doi:10.1152/ajpheart.00043.2015

Cited by 41 publications

(38 citation statements)

References 46 publications

(54 reference statements)

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“…Ray et al showed MGO inhibits electron flow through complex I leading to mitochondrial dysfunction [33, 34]. In addition, some reports revealed that AGEs can also trigger mitochondrial dysfunction [35, 36]. These studies provide a strong support for our study about MGO-induced mitochondrial dysfunction.…”

Section: Discussionsupporting

confidence: 77%

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

Liu¹,

Meng²,

Chen³

et al. 2017

Cell Physiol Biochem

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Background/Aim: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC’s dermal protection in human HaCaT keratinocytes. Methods: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function. Results: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-κB activation, MMP-9 upregulation and inflammatory injury in HaCaT cells. Conclusion: The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future.

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Section: Discussionsupporting

confidence: 77%

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

Liu¹,

Meng²,

Chen³

et al. 2017

Cell Physiol Biochem

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“…Moreover, AGEs have been shown to induce the expression of ENaC via activation of SGK1 [57]. Recent evidence in mice suggests there is RAGE upregulation in cardiomyocytes that contributes to cardiomyopathy [58]. Herein, we show that myocardial AGE expression is increased in DbC and DbE, compared to CkC, and observe that it is widely distributed throughout the LV wall, including in the vasculature.…”

Section: Discussionmentioning

confidence: 60%

Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes

Habibi

Aroor

Sowers

et al. 2017

Cardiovasc Diabetol

219

176

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Obese and diabetic individuals are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction. The impairments in diastolic relaxation are especially pronounced in obese and diabetic women and predict future cardiovascular disease (CVD) events in this population. Recent clinical data suggest sodium glucose transporter-2 (SGLT2) inhibition reduces CVD events in diabetic individuals, but the mechanisms of this CVD protection are unknown. To determine whether targeting SGLT2 improves diastolic relaxation, we utilized empagliflozin (EMPA) in female db/db mice. Eleven week old female db/db mice were fed normal mouse chow, with or without EMPA, for 5 weeks. Blood pressure (BP), HbA1c and fasting glucose were significantly increased in untreated db/db mice (DbC) (P < 0.01). EMPA treatment (DbE) improved glycemic indices (P < 0.05), but not BP (P > 0.05). At baseline, DbC and DbE had already established impaired diastolic relaxation as indicated by impaired septal wall motion (>tissue Doppler derived E′/A′ ratio) and increased left ventricular (LV) filling pressure (

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“…An underlying mechanistic theme of the smoke-related disease states outlined in this review is chronic inflammation, in which RAGE is a key modulator. Essential to understanding the clear link between RAGE and disease progression is the key concept that RAGE expression is increased by exposure to tobacco smoke [5,209,210,211,212] and the induction of RAGE causes inflammatory disease symptoms similar or identical to the ones described herein [23,195,213,214,215,216,217]. …”

Section: Rage: a Plausible Unifying Mechanismmentioning

confidence: 95%

“…Of note, RAGE is most abundantly expressed in the lung, the tissue in which it was initially discovered. Although RAGE is predominantly expressed in the lung, it is detectable in a variety of tissues including the heart, brain, placenta, liver, kidney, pancreas, small intestine, and colon [4,5]. RAGE is a pattern recognition cell surface receptor that binds many endogenous and exogenous entities such as S100/calgranulins [218], amyloid-β-peptide [219], HMGB-1 [220], and AGEs [221].…”

Section: Rage: a Plausible Unifying Mechanismmentioning

confidence: 99%

“…Of note, RAGE is most abundantly expressed in the lung, the tissue in which it was initially discovered. Although RAGE is predominantly expressed in the lung, it is detectable in a variety of tissues including the heart, brain, placenta, liver, kidney, pancreas, small intestine, and colon [4,5]. This review will highlight the current understanding related to a subset of smoke-related pathologies and conclude with evidence that supports a role for RAGE in disease manifestation.…”

Section: Introductionmentioning

confidence: 99%

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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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Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner

Cited by 41 publications

References 46 publications

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes

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

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