Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

Fujita, Yugo; Yano, Toshiyuki; Kanamori, Hiromitsu; Nagahara, Daigo; Muranaka, Atsuko; Kouzu, Hidemichi; Mochizuki, Atsushi; Koyama, Masayuki; Nagano, Nobutaka; Fujito, Takefumi; Nishikawa, Ryo; Kamiyama, Naoyuki; Tanaka, Marenao; Kuno, Atsushi; Tanno, Masaya; Miura, Tetsuji

doi:10.1002/ehf2.14059

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…tested whether phosphorylation of mixed lineage kinase domain‐like protein (MLKL) is associated with the progression of DCM. The results suggest that increased localization of nuclear phosphorylated MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM 62 …”

Section: Preclinical and Translational Investigationsmentioning

confidence: 81%

“…The results suggest that increased localization of nuclear phosphorylated MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM. 62 Although the nitric oxide (NO) signalling pathway has been implicated in HFpEF, the involvement of this pathway in the pathophysiology of HFpEF is not entirely clear. Piatek et al conducted a clinical study on 73 prospectively enrolled patients.…”

Section: Preclinical and Translational Investigationsmentioning

confidence: 99%

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A year in heart failure: updates of clinical and preclinical findings

et al. 2023

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We witnessed major advances in the management of heart failure (HF) in 2022. Results of recent clinical and preclinical investigations aid preventive strategies, diagnostic efforts, and therapeutic interventions, and collectively, they hold promises for a more effective HF care for the near future. Accordingly, currently available information extends the 2021 European Society of Cardiology guidelines and provides a solid background for the introduction of improved clinical approaches in the number of HF‐related cases. Elaboration on the relationships between epidemiological data and risk factors lead to better understanding of the pathophysiology of HF with reduced ejection fraction and HF with preserved ejection fraction. The clinical consequences of valvular dysfunctions are increasingly interpreted not only in their haemodynamic consequences but also in association with their pathogenetic factors and modern corrective treatment possibilities. The influence of coronavirus disease 2019 pandemic on the clinical care of HF appeared to be less intense in 2022 than before; hence, this period allowed to refine coronavirus disease 2019 management options for HF patients. Moreover, cardio‐oncology emerges as a new subdiscipline providing significant improvements in clinical outcomes for oncology patients. Furthermore, the introduction of state‐of‐the‐art molecular biologic methods, multi‐omic approaches forecast improved phenotyping and precision medicine for HF. All above aspects are addressed in this article that highlights a selection of papers published in ESC Heart Failure in 2022.

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Section: Preclinical and Translational Investigationsmentioning

confidence: 81%

Section: Preclinical and Translational Investigationsmentioning

confidence: 99%

A year in heart failure: updates of clinical and preclinical findings

et al. 2023

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“…Then, the activated MLKL is multimerized within the cytoplasm, giving rise to the formation of a necrosome [21]. A crucial role of the nuclear-cytoplasmic shuttling of MLKL in pro-necroptotic signaling has been unveiled recently in animal models and patients [35,36]. The association of MLKL with the cell membrane in necroptotic death is preceded by the translocation of phosphorylated MLKL to the nucleus [37].…”

Section: Discussionmentioning

confidence: 99%

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Fan,

Lin,

Chen

et al. 2024

Molecules

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Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid glycoside compound that is extracted from Ixeris sonchifolia (Bge.) Hance, and it is a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the neuroprotective effect of LGU was investigated in an oxygen glucose deprivation (OGD) model and a middle cerebral artery occlusion (MCAO) rat model. In vitro, LGU was found to effectively improve the OGD-induced decrease in neuronal viability and increase in neuronal death by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) leakage rate assay, respectively. LGU was also found to inhibit OGD-induced intracellular Ca2+ overload, adenosine triphosphate (ATP) depletion, and mitochondrial membrane potential (MMP) decrease. By Western blotting analysis, LGU significantly inhibited the OGD-induced increase in expressions of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). Moreover, molecular docking analysis showed that LGU might bind to RIP3 more stably and firmly than the RIP3 inhibitor GSK872. Immunofluorescence combined with confocal laser analyses disclosed that LGU inhibited the aggregation of MLKL to the nucleus. Our results suggest that LGU ameliorates OGD-induced rat primary cortical neuronal injury via the regulation of the RIP3/MLKL signaling pathway in vitro. In vivo, LGU was proven, for the first time, to protect the cerebral ischemia in a rat middle cerebral artery occlusion (MCAO) model, as shown by improved neurological deficit scores, infarction volume rate, and brain water content rate. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia.

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Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

et al. 2022

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Aims The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain‐like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. Methods and results Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p‐MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p‐MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = −0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p‐MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = −0.360, P = 0.014). During a median follow‐up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p‐MLKL expression levels, patients were divided into two groups by using the median value of nuclear p‐MLKL or intercalated disc p‐MLKL. A group with high nuclear p‐MLKL level (H‐nucMLKL group) had a higher adverse event rate than did a group with low nuclear p‐MLKL level (L‐nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan–Meier survival curves showed that the adverse event‐free survival rate was lower in the H‐nucMLKL group than in the L‐nucMLKL group (P = 0.019 by the log‐rank test). Such differences were not detected between groups divided by a median value of intercalated disc p‐MLKL. In δ‐sarcoglycan‐deficient (Sgcd−/−) mice, a model of DCM, total p‐MLKL and nuclear p‐MLKL levels were higher than in wild‐type mice. Conclusion The results suggest that increased localization of nuclear p‐MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

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Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

Cited by 6 publications

References 55 publications

A year in heart failure: updates of clinical and preclinical findings

A year in heart failure: updates of clinical and preclinical findings

Luteolin-7-O-β-d-glucuronide Ameliorates Cerebral Ischemic Injury: Involvement of RIP3/MLKL Signaling Pathway

Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

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