Histone deacetylase HDAC4 participates in the pathological process of myocardial ischemia-reperfusion injury via MEKK1/JNK pathway by binding to miR-206

Li, Qingman; Zhu, Lihua; Niu, Fangqing; Li, Qingmin; Che, Wang; Yang, Haiyan; Gao, Chuanyu

doi:10.1038/s41420-021-00601-1

Cited by 7 publications

(3 citation statements)

References 52 publications

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“…Furthermore, in vitro investigations presented that HDAC4 negatively regulated the polarization of Th17 cells in naïve CD4 + T cells of patients with AS, which was in line with a previous study focusing on inflammatory bowel disease (16). We deduced that HDAC4 might regulate some pathways, such as the c-Jun N-terminal kinase pathway, to regulate the production of several cytokines, including IL-1β, IL-6, IL-23, etc., which were critical for the polarization of CD4 + T cells into Th17 (37,38). However, this should be further verified.…”

Section: Discussionmentioning

confidence: 89%

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis

Dou

Jiang

et al. 2022

Front. Med.

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PurposeHistone deacetylase 4 (HDAC4) regulates the progression of autoimmune diseases. This study aimed to further investigate the correlation between HDAC4 and Th cells, inflammation, disease activity, and treatment response in patients with ankylosing spondylitis (AS).MethodsA total of 132 active patients with AS were enrolled, of whom 54 patients received TNF inhibitor (TNFi) and 78 patients received NSAID. Serum HDAC4 was measured by ELISA in patients with AS before treatment (W0) and at week (W)4, W8, and W12 after treatment. Meanwhile, serum HDAC4 was detected in 30 patients with osteoarthritis and in 30 healthy controls (HCs) by ELISA. Besides, naïve CD4+ T cells from patients with AS were isolated, followed by modulation of HDAC4 and then polarization toward Th1, Th2, and Th17.ResultsHistone deacetylase 4 was reduced in patients with AS compared with HCs and patients with osteoarthritis (both P < 0.01). In patients with AS, HDAC4 was negatively correlated with TNF (P < 0.001), IL-1β (P = 0.003), Th17 proportion (P = 0.008), C-reactive protein (P < 0.001), and ASDAS (P = 0.038), but not with IL-6, Th1 proportion, or other characteristics. Meanwhile, HDAC4 increased from W0 to W12 (P < 0.001); HDAC4 at W8 (P = 0.014) and W12 (P = 0.006) was raised in ASAS40-response patients than ASAS40-non-response patients; further subgroup analysis showed that HDAC4 at W12 was higher in ASAS40-response patients than ASAS40-non-response patients (P = 0.016) in the TNFi-treated group, but not in the NSAID-treated group. In addition, HDAC4 negatively regulated the polarization of naïve CD4+ T cells toward Th17 (P < 0.01), but not Th1 or Th2.ConclusionHistone deacetylase 4 is associated with lower inflammation, and the disease activity negatively regulates Th17 polarization, whose increment after treatment reflects favorable outcomes in patients with AS.

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Section: Discussionmentioning

confidence: 89%

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis

Dou

Jiang

et al. 2022

Front. Med.

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“…Histone deacetylases (HDACs) are enzymes that play a critical role in cardiac function and ischemic injury ( 41 ). Patients with heart failure and atherosclerosis have high levels of HDAC-4 expression ( 42 ).…”

Section: Resultsmentioning

confidence: 99%

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Quagliariello,

Passariello,

Bisceglia

et al. 2024

Front. Cardiovasc. Med.

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BackgroundImmune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events.MethodsHuman cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens.ResultsBoth combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies.ConclusionsData of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

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“…However, cardiac levels of HDAC4 were significantly downregulated by leucine supplementation. HDAC4 has been described as a key protein promoting myocardial damage [16,17,[46][47][48], and HDAC inhibition has demonstrated protective effects on mitochondrial homeostasis and performance [47]. Thus, enhanced mitochondrial respiratory function might have been a result of HDAC4 inhibition.…”

Section: Limitationsmentioning

confidence: 99%

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition

Alves,

Schauer,

Augstein

et al. 2023

Cells

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Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-β1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF.

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Histone deacetylase HDAC4 participates in the pathological process of myocardial ischemia-reperfusion injury via MEKK1/JNK pathway by binding to miR-206

Cited by 7 publications

References 52 publications

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition

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