TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Ma, Xiucui; Rawnsley, David R.; Kovács, Attila; Islam, Moydul; Murphy, John T.; Zhao, Chen; Kumari, Ms. Dimple; Foroughi, Layla; Liu, Haiyan; Qi, Kevin; Diwan, Aaradhya; Hyrc, Krzysztof L.; Evans, Sarah; Satoh, Takashi; French, Brent A.; Margulies, Kenneth B.; Javaheri, Ali; Razani, Babak; Mann, Douglas L.; Mani, Kartik; Diwan, Abhinav

doi:10.1016/j.jacbts.2021.12.002

Cited by 15 publications

(22 citation statements)

References 52 publications

(111 reference statements)

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“…First, human samples from patients with anthracycline cardiotoxicity demonstrate reduced TRAF2 protein levels. This is contradistinction to what has recently been described by Ma et al, 54 who showed increased mitochondrial TRAF2 levels in heart tissue from patients with a history of ischemic cardiomyopathy. Second, although in both cases the human myocardial tissue was obtained years from the inciting event (either myocardial ischemia or anthracycline exposure), it appears that there are specific molecular changes that persist, unique to anthracycline exposure, that also correspond to what we have observed both in vitro and in the animal models.…”

Section: Discussioncontrasting

confidence: 96%

“…This notion is based on a recent report demonstrating a role for TRAF2 in clearing damaged mitochondria via mitophagy during myocardial ischemia/ reperfusion. 54 Therefore, selectively balancing the E3ligase activity of TRAF2 as shown in the present study may prove beneficial in mitigating cardiac injury and ven-tricular dysfunction in patients with cancer undergoing DOX treatment.…”

Section: Dhingra Et Almentioning

confidence: 76%

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Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy

et al. 2022

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Background: Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα–TRAF2–NF-κB signaling in the pathogenesis of DOX cardiotoxicity. Methods: Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg −1 ·wk −1 ) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell–derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability. Results: In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T–adeno-associated virus 9–TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX. Conclusions: Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.

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Section: Discussioncontrasting

confidence: 96%

Section: Dhingra Et Almentioning

confidence: 76%

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy

et al. 2022

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“…MaxBlock is a commercialized AF treatment designed to reduce background AF on paraffin-embedded and frozen tissue sections. It has been used to diminish AF in several tissues, such as the liver [ 56 ], heart [ 57 ], lung [ 58 , 59 ], pancreas [ 60 ], and skin [ 61 ] tissues.…”

Section: Discussionmentioning

confidence: 99%

Characterizing and Quenching Autofluorescence in Fixed Mouse Adrenal Cortex Tissue

Sakr

Glazova

Shevkova

et al. 2023

IJMS

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Tissue autofluorescence of fixed tissue sections is a major concern of fluorescence microscopy. The adrenal cortex emits intense intrinsic fluorescence that interferes with signals from fluorescent labels, resulting in poor-quality images and complicating data analysis. We used confocal scanning laser microscopy imaging and lambda scanning to characterize the mouse adrenal cortex autofluorescence. We evaluated the efficacy of tissue treatment methods in reducing the intensity of the observed autofluorescence, such as trypan blue, copper sulfate, ammonia/ethanol, Sudan Black B, TrueVIEWTM Autofluorescence Quenching Kit, MaxBlockTM Autofluorescence Reducing Reagent Kit, and TrueBlackTM Lipofuscin Autofluorescence Quencher. Quantitative analysis demonstrated autofluorescence reduction by 12–95%, depending on the tissue treatment method and excitation wavelength. TrueBlackTM Lipofuscin Autofluorescence Quencher and MaxBlockTM Autofluorescence Reducing Reagent Kit were the most effective treatments, reducing the autofluorescence intensity by 89–93% and 90–95%, respectively. The treatment with TrueBlackTM Lipofuscin Autofluorescence Quencher preserved the specific fluorescence signals and tissue integrity, allowing reliable detection of fluorescent labels in the adrenal cortex tissue. This study demonstrates a feasible, easy-to-perform, and cost-effective method to quench tissue autofluorescence and improve the signal-to-noise ratio in adrenal tissue sections for fluorescence microscopy.

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“…However, our group reiterated the cytoprotective effects of TRAF2 may have been afforded via crosstalk between canonical and noncanonical NF-kB signaling pathways (Evans et al, 2018). A more recent study noted that TRAF2 maintains myocardial homeostasis through facilitation of cardiac myocyte mitophagy thus preventing inflammation and cell death (Ma et al, 2022). We also found that aortic ejection time were significantly prolonged in the TRAF2 mice (Figure 3D).…”

Section: Discussionmentioning

confidence: 99%

“…However, other studies have suggested that cardiac function was improved after myocardial infarction in absence of NF-kB p50 subunit (Frantz et al, 2006), that suppressing NF-kB with oligonucleotide decoys reduces ischemia related myocardial injury (Tranter et al, 2012), and that TRAF2 mediates enhanced cardiac hypertrophy via activation of AKT/GSK3β signaling (Huang et al, 2014). Regardless, overexpression of TRAF2 was found to have cardioprotective role in myocardial injury and perhaps can be novel therapeutic strategy in cardiomyopathy (Ma et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Hemodynamics in Mice with Tumor Necrosis Factor Receptor - Associated Factor 2 Mediated Cytoprotection in the Heart

Marshall

Neikirk

Vue

et al. 2022

Preprint

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Many studies in mice have demonstrated that cardiac-specific innate immune signaling pathways can be reprogrammed to modulate inflammation in response to myocardial injury and improve outcomes. In these studies, however, the standard parameters of left ventricular (LV) ejection fraction, fractional shortening, and end-diastolic diameter, among others, to assess cardiac function depend upon loading conditions and therefore do not completely reflect the contractile function of the heart. A true measure of global cardiac efficiency should include of the interaction between the ventricle and the aorta (ventriculo-vascular coupling, VVC) as well as measures of aortic impedance and pulse wave velocity. We measured cardiac Doppler velocities, blood pressures, along with VVC, aortic impedance, and pulse wave velocity to evaluate global cardiac function in mouse model of cardiac-restricted low levels TRAF2 overexpression that conferred cytoprotection in the heart. While response to myocardial infraction and reperfusion was improved in the TRAF2 overexpressed mice, we found that TRAF2 mice had significantly lower cardiac systolic velocities and accelerations, diastolic atrial velocity, lower aortic pressures and rate-pressure product, lower LV contractility and relaxation, and lower stroke work when compared to littermate control mice. Also, we found significantly longer aortic ejection time, isovolumic contraction and relaxation times, and significantly higher mitral early/atrial ratio, myocardial performance index, and ventricular vascular coupling in the TRAF2 overexpression mice compared to their littermate controls. We found no significant differences in the aortic impedance and pulse wave velocity. While the reported tolerance to ischemic insults in TRAF2 overexpression mice may suggest enhanced cardiac reserve, our results indicate a diminished cardiac function in these mice.

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TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Cited by 15 publications

References 52 publications

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy

Characterizing and Quenching Autofluorescence in Fixed Mouse Adrenal Cortex Tissue

Cardiovascular Hemodynamics in Mice with Tumor Necrosis Factor Receptor - Associated Factor 2 Mediated Cytoprotection in the Heart

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