Interleukin‐5 deletion promotes sepsis‐induced
            M1
            macrophage differentiation, deteriorates cardiac dysfunction, and exacerbates cardiac injury via the
            NF‐κB
            p65 pathway in mice

Background. Numerous studies have demonstrated that the inflammatory response is involved in the progression of lipopolysaccharide- (LPS-) induced myocardial cell apoptosis. Accumulating evidence has shown that thyroxine participates in diseases by downregulating the inflammatory response. This study aimed at investigating whether thyroxine alleviates LPS-induced myocardial cell apoptosis. Methods. Bone marrow-derived macrophages (Mø) were treated with LPS and thyroxine, and Mø differentiation and Mø-related cytokine expression were measured. The effect of Mø differentiation on mouse cardiomyocyte (MCM) apoptosis was also detected in vitro. In addition, C57BL/6 mice underwent thyroidectomy and were treated with LPS 35 days later; subsequently, Mø differentiation and myocardial cell apoptosis in hearts were analyzed. To determine whether the nuclear factor-kappa B (NF-κB) p65 pathway mediates the effect of thyroxine on Mø differentiation and myocardial cell apoptosis, the specific NF-κB p65 pathway inhibitor JSH-23 was administered to mice that underwent a thyroidectomy. Results. Levothyroxine treatment significantly reduced the activation of the NF-κB p65 pathway, decreased M1 macrophage (Mø1) differentiation and Mø1-related cytokine mRNA levels in LPS-treated Mø, and increased M2 macrophage (Mø2) differentiation and Mø2-related cytokine mRNA expression. The protective effects of levothyroxine on MCM apoptosis mediated by LPS-treated Mø were alleviated by JSH-23. In mice, thyroidectomy aggravated LPS-induced cardiac injury and cardiac dysfunction, further promoted NF-κB p65 activation, and increased cardiac Mø1 expression and myocardial cell apoptosis but decreased cardiac Mø2 expression. JSH-23 treatment significantly ameliorated the thyroidectomy-induced increases in myocardial cell apoptosis and Mø differentiation. Conclusions. Thyroxine alleviated the Mø1/Mø2 imbalance, reduced the inflammatory response, decreased myocardial cell apoptosis, and protected against cardiac injury and cardiac dysfunction in LPS-treated mice. Thyroxine may be a novel therapeutic strategy to prevent and treat LPS-induced cardiac injury.

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Anti-Interleukin-16-Neutralizing Antibody Attenuates Cardiac Inflammation and Protects against Cardiac Injury in Doxorubicin-Treated Mice

Mediators of Inflammation ◽

10.1155/2021/6611085 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Jianwei Zhang ◽

Zicong Yang ◽

Zhishan Liang ◽

Mengjie Wang ◽

Changxing Hu ◽

...

Keyword(s):

Troponin T ◽

Cardiac Injury ◽

Neutralizing Antibody ◽

Serum Levels ◽

Cardiomyocyte Apoptosis ◽

Macrophage Differentiation ◽

Cardiac Inflammation ◽

Pathway Activation ◽

M1 Macrophage

Background. Interleukin-16 (IL-16) is an important inflammatory regulator and has been shown to have a powerful effect on the regulation of the inflammatory response. Cardiac inflammation has been reported to be closely related to doxorubicin- (DOX-) induced cardiac injury. In this study, the role of IL-16 in DOX-induced cardiac injury and the possible mechanisms were examined. Methods. Cardiac IL-16 levels were first measured in DOX- or saline-treated mice. Additionally, mice were pretreated with the anti-IL-16-neutralizing antibody (nAb) or isotype IgG for 1 day and further administered DOX or saline for 5 days. Then, cardiac injury, cardiac M1 macrophage levels, and cardiomyocyte apoptosis were analyzed. The effects of the anti-IL-16 nAb on macrophage differentiation and cardiomyocyte apoptosis were also investigated in vitro. Results. DOX administration increased IL-16 expression in cardiac macrophages compared with that of saline treatment. The anti-IL-16 nAb significantly decreased serum levels of lactate dehydrogenase (LDH), myocardial-bound creatine kinase (CK-MB), and cardiac troponin T (cTnT) and elevated cardiac function in DOX-induced mice. Treatment with the anti-IL-16 nAb also reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. In cell studies, the anti-IL-16 nAb also reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages. Conclusions. The anti-IL-16 nAb protects against DOX-induced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury.

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Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis

Journal of Intensive Care ◽

10.1186/s40560-021-00548-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Dilip Jayasimhan ◽

Simon Foster ◽

Catherina L. Chang ◽

Robert J. Hancox

Keyword(s):

Systematic Review ◽

Acute Respiratory Distress Syndrome ◽

Intensive Care ◽

Cardiac Dysfunction ◽

Distress Syndrome ◽

Troponin I ◽

Meta Analysis ◽

Cardiac Injury ◽

Cardiac Biomarkers ◽

Risk Of Death

Abstract Background Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality. Methods A systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity. Results Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07). Conclusion Biomarkers of cardiac stretch are associated with increased mortality in ARDS.

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Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

Cells ◽

10.3390/cells9040938 ◽

2020 ◽

Vol 9 (4) ◽

pp. 938

Author(s):

Yi-Hsuan Lin ◽

Yi-Hsun Wang ◽

Yi-Jen Peng ◽

Feng-Cheng Liu ◽

Gu-Jiun Lin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Messenger Rna ◽

Molecular Mechanisms ◽

Macrophage Polarization ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Macrophage ◽

Macrophage Differentiation ◽

Macrophage Cells ◽

M1 Macrophage ◽

Interleukin 26

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

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Seabuckthorn Attenuates Cardiac Dysfunction and Oxidative Stress in Isoproterenol-Induced Cardiotoxicity in Rats

International Journal of Toxicology ◽

10.1177/1091581811417898 ◽

2011 ◽

Vol 30 (6) ◽

pp. 671-680 ◽

Cited By ~ 13

Author(s):

Salma Malik ◽

Sameer Goyal ◽

Shreesh Kumar Ojha ◽

Saurabh Bharti ◽

Saroj Nepali ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Antioxidant Activities ◽

Cardiac Injury ◽

Radical Scavenging ◽

Myocardial Necrosis ◽

Myocardial Damage ◽

Ultrastructural Changes ◽

And Oxidative Stress ◽

Preventive Role

We investigated the effects of seabuckthorn (SBT) oil in isoproterenol (ISO)-induced cardiotoxicity with reference to hemodynamic, antioxidant, histopathological, and ultrastructural parameters. Rats were administered SBT oil (5, 10, and 20 mL/kg per d) or vehicle orally for 30 days along with ISO (85 mg/kg, subcutaneously, at 24-hour interval) on 29th and 30th day. On 31st day, ISO control rats showed cardiac dysfunction, increased lipid peroxidation, depletion of cardiac injury marker enzymes, and antioxidant activities. Myocardial necrosis, edema, and inflammation were evident from the light microscopic and ultrastructural changes. Seabuckthorn oil at the dose of 20 mL/kg per d significantly modulates hemodynamic and antioxidant derangements. The preventive role of SBT oil on ISO-induced cardiotoxicity was reconfirmed by histopathological and ultrastructural examinations. Thus, the present study reveals that SBT oil mitigates myocardial damage in ISO-induced cardiac injury in rats by maintaining hemodynamic, biochemical, histopathological, and ultrastructural perturbations owing to its free radical scavenging and antioxidant activities.

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Extracellular SPARC improves cardiomyocyte contraction during health and disease

10.1101/492363 ◽

2018 ◽

Author(s):

Sophie Deckx ◽

Daniel M. Johnson ◽

Marieke Rienks ◽

Paolo Carai ◽

Elza van Deel ◽

...

Keyword(s):

Cardiac Function ◽

Cardiac Dysfunction ◽

Matrix Protein ◽

Contractile Function ◽

Ex Vivo ◽

Cardiac Fibroblasts ◽

Cardiac Injury ◽

Coxsackie Virus ◽

Extracellular Matrix Protein

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and in lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly improves cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.

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Interleukin-6 knockout reverses macrophage differentiation imbalance and alleviates cardiac dysfunction in aging mice

Aging ◽

10.18632/aging.103749 ◽

2020 ◽

Vol 12 (20) ◽

pp. 20184-20197

Author(s):

Yuan Wang ◽

Shan Zhu ◽

Wen Wei ◽

Yi Tu ◽

Chuang Chen ◽

...

Keyword(s):

Interleukin 6 ◽

Cardiac Dysfunction ◽

Macrophage Differentiation

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Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

eLife ◽

10.7554/elife.54298 ◽

2020 ◽

Vol 9 ◽

Author(s):

Andrea Ruiz-Velasco ◽

Min Zi ◽

Susanne S Hille ◽

Tayyiba Azam ◽

Namrita Kaur ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Cardiac Dysfunction ◽

Cardiac Injury ◽

Induced Pluripotent Stem Cell ◽

Mitogen Activated Protein Kinase ◽

Rat Cardiomyocytes ◽

Functional Studies ◽

Mitogen Activated Protein ◽

Myocardial Insulin Resistance

Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.

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Role of PI3K/AKT/mTOR Pathway Associated Oxidative Stress and Cardiac Dysfunction in Takotsubo Syndrome

Current Neurovascular Research ◽

10.2174/1567202617666191223144715 ◽

2020 ◽

Vol 17 (1) ◽

pp. 35-43

Author(s):

Shan Mao ◽

Xianghong Luo ◽

Yu Li ◽

Chaorong He ◽

Fuhua Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Myocardial Dysfunction ◽

Cardiac Injury ◽

Protective Role ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Protective Effects ◽

Takotsubo Syndrome ◽

Akt Inhibitor

Introduction: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, but the accurate cause of this syndrome is still unknown. Methods: β-adrenergic agonist isoproterenol (ISO) is used to establish the TTS rats model. TTS rats were treated with or without LY294002 or Rapamycin. The rat cardiomyoblast cell line H9C2 was subjected to infect with constitutively active Akt (myr-Akt) or dominant-negative mutant Akt (dn-Akt) and then, treated with ISO. Cell apoptosis was assessed using the Bax/ Bcl-2 ratio. In addition, reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE). Mitochondrial superoxide generation and membrane potential were assayed by MitoSOX and JC-1 fluorescence intensity. Results: ISO might induce the erratic acute cardiac dysfunction and overexpression of PI3K/AKT/mTOR. Moreover, it also increased the oxidative stress and apoptosis in TTS rats. The Akt inhibitor significantly reversed the cardiac injury effect, which triggered by ISO treatment. In H9C2 cells, the inhibition of Akt provides a protective role against ISO-induced injury by reducing oxidative stress, apoptosis and mitochondrial dysfunction. Conclusion: This study provided new insight into the protective effects of myocardial dysfunction in TTS rats via chronic inhibition of the PI3K/AKT/mTOR expression, which could reduce mitochondrial ROS and oxidative stress-induced apoptosis. PI3K/AKT/mTOR inhibitor could be a therapeutic target to treat cardiovascular dysfunction induced by stress cardiomyopathy.

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Abstract P45: White Blood Cell Counts in Aneurysmal Subarachnoid Hemorrhage Patients as a Predictor of Cardiac Injury

Stroke ◽

10.1161/str.52.suppl_1.p45 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Tiffany Cheng ◽

Joseph R Geraghty ◽

Neil S Saini ◽

Yonatan Hirsch ◽

Tyler J Lung ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cardiac Dysfunction ◽

Leukocyte Count ◽

Cardiac Injury ◽

Total Leukocyte Count ◽

Monocyte Count ◽

Cell Counts ◽

Leukocyte Counts ◽

Blood Leukocyte ◽

The Relationship

Introduction: Up to 50% of subarachnoid hemorrhage (SAH) patients develop cardiac injury. The relationship between early systemic inflammation and cardiac injury after SAH is unknown. Here we examined changes in blood leukocyte counts and their relationship to cardiac dysfunction. Methods: We reviewed the medical records of 288 SAH patients admitted to our Comprehensive Stroke Center. Patients were dichotomized based on elevated (≥0.04ng/mL) or normal (<0.04ng/mL) troponin I (TnI). Demographics and labs from admission were then compared among the two groups by Chi-Square or Mann-Whitney test. Ejection fraction (EF) was stratified into low (<50%), normal (50-70%), or high (>70%) from echocardiogram data. We performed univariate and multivariate logistic regression to establish the relationship between blood leukocyte counts and cardiac injury. Results: Of 288 SAH patients, 241 had TnI levels performed at the time of admission and 119 (49.4%) of these had elevated TnI on admission. Patients with elevated TnI were significantly older, had higher grade SAH, abnormal EF, and were more likely to have hypertension and dyslipidemia. 10 (4.1%) had low EF while 58 (24.1%) had high EF on admission echocardiogram. In univariate analysis, total leukocyte count (p<0.0001), absolute neutrophil count (p=0.037), absolute monocyte count (p=0.014), and neutrophil-lymphocyte ratio (p=0.010) were associated with elevated TnI. Multivariate analysis adjusting for covariates showed that only total leukocyte count remained a significant predictor of elevated TnI (OR = 1.104, 95% CI= 1.020 - 1.195; p=0.014). Receiver operating characteristic (ROC) analysis demonstrated that adjusted total leukocyte count distinguishes between SAH patients with normal and elevated TnI (area under the curve = 0.787, p=0.001), with the optimal cutoff being 0.521 (sensitivity of 67.0% and specificity of 80.6%). Conclusions: Blood total leukocyte count is an independent predictor of cardiac injury in SAH patients. This highlights the role of inflammation in mediating cardiac dysfunction after brain hemorrhage, and raises questions regarding the potential of anti-inflammatory therapy for cardioprotection in SAH.

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