Acute myocardial infarction induced increases in plasma tumor necrosis factor-α and interleukin-10 are associated with the activation of poly(ADP-ribose) polymerase of circulating mononuclear cell

doi:10.1016/j.ijcard.2007.06.069

International Journal of Cardiology

Volume 123, Issue 3, 24 January 2008, Pages 366-368

https://doi.org/10.1016/j.ijcard.2007.06.069 Get rights and content

Abstract

Systemic inflammatory response to acute myocardial infarction (AMI) is detrimental to heart function. In this study, we proved that poly(ADP-ribose) polymerase (PARP) activity of circulating mononuclear cell (MNC) increased significantly in post-AMI patients. MNC PARP activity was correlated positively with plasma tumor necrosis factor-α (TNF-α) level, interleukin-10 (IL-10) level and the ratio of plasma TNF-α/IL-10 respectively. On the contrary, MNC PARP activity was correlated negatively with left ventricular ejection fraction and left ventricular fractional shortening which were measured with echocardiography in the same day when blood sample was collected. These results implicated that activation of PARP in MNC contributes to the increases in plasma TNF-α and IL-10 and is associated with systolic dysfunction of heart after AMI.

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The therapeutic efficacy is sustained across multiple animal species (rodent and large animal), exhibits a good therapeutic window, and extends into multiple relevant outcome variables (infarct size, cardiac enzymes, contractility, inflammatory mediators, mononuclear cell infiltration into the heart and activation of circulating leukocytes). There are also multiple lines of human data showing PARP activation in the heart in various cardiac diseases (or diseases with cardiac involvement) including acute myocardial infarction and revascularization, where PARP activation has been demonstrated in circulating leukocytes (Tóth-Zsámboki et al., 2006; Yao et al., 2008), cardiopulmonary bypass (Ramlawi et al., 2006) as well as septic shock (Soriano et al., 2006), aortic valve stenosis (Nagy et al., 2012), diabetic cardiomyopathy and chronic heart failure (Pillai et al., 2005a,b; Molnár et al., 2006). Taken together, the data are in support of further exploration of this indication for the clinical development of PARP inhibitors.
The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.
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The ROC analysis displays a high performance for both ET-1 and MCP-1 as event-specific markers in such circumstances. Finally, our results show that serum levels of both vasoconstrictive and inflammatory mediators were higher in the reference population compared with healthy volunteers, confirming previous findings (3–7). In the last decade, research has focused on identifying inflammatory signaling pathways specifically involved in ACS (8–11).
We sought to assess whether emotional stress-induced acute coronary syndrome (ACS) is mediated by increased inflammatory and vasoconstrictive mediators.
The World Cup soccer 2006 has been shown to provoke levels of stress sufficient to increase the incidence of ACS. However, the mechanisms by which stress translates into vascular injury up to plaque rupture still remain elusive.
Serum levels of soluble CD40L (sCD40L), soluble vascular cell adhesion molecule (sVCAM)-1, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hsCRP), regulated on activation, normal T-cell expressed and secreted (RANTES), and endothelin (ET)-1 were determined in patients who experienced an ACS during World Cup matches, in ACS reference patients (not associated with emotional stress), and in healthy volunteers. Correlations and receiver-operating characteristic curves were calculated to develop multivariable analysis and to investigate the diagnostic value of each parameter.
The sCD40L, sVCAM-1, MCP-1, TNF-α, and ET-1 were significantly higher in study patients compared with the reference group. The hsCRP was similar in both groups, whereas RANTES was decreased in study patients. A positive correlation was found between ET-1 and soccer-induced enhanced levels of sCD40L, sVCAM-1, MCP-1, and TNF-α. Receiver-operating characteristic analysis displayed high performance of both MCP-1 and ET-1 as a measure to discriminate between stress-induced ACS and ACS controls.
Stress-induced ACS is associated with a profound increase of inflammatory and vasoconstrictive mediators. The evaluation of a targeted drug delivery, such as anti-inflammatory agents, ET-1 receptor antagonists, or inhibition of endothelin-converting enzyme is warranted to reduce stress-mediated cardiovascular morbidity.
Poly(ADP-ribose) activation in circulating cells in human myocardial infarction
2009, International Journal of Cardiology
Response letter "AMI induced activation of poly (ADP-ribose) polymerase in circulating monoclear cell"
2009, International Journal of Cardiology
Activation and Overexpression of PARP-1 in Circulating Mononuclear Cells Promote TNF-α and IL-6 Expression in Patients with Unstable Angina
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PARP-1 normally functions in DNA repair and also participates in the transcriptional regulation of genes via two mechanisms: (1) PARP-1 promotes decondensation of higher-order chromatin structures through poly(ADP-ribosyl)ation of histones; and (2) PARP-1 acts as a component of enhancer/promoter regulatory complexes (5,6). It has been shown that activation of PARP-1 promotes transcription of TNF-α and IL-6 in monocytes/macrophages (7,8). However, it remains unclear whether PARP-1 is activated in patients with UA.
Proinflammatory cytokines are involved in the development of unstable angina (UA). Poly(ADP-ribose) polymerase-1 (PARP-1) contributes importantly to regulating the transcription of inflammatory cytokines. This study aims to investigate the relationship of PARP-1 in circulating mononuclear cells (MNCs) and plasma TNF-α and IL-6 in UA patients and to elucidate the mechanism that PARP-1 promotes TNF-α and IL-6 expression via NF-κB pathway.
Twenty six Braunwald class IIIB UA patients, 25 stable angina patients and 25 healthy volunteers were enrolled in this study. Plasma TNF-α and IL-6 were determined with ELISA. Circulating MNCs were analyzed for PARP activity, PARP-1 expression and NF-κB DNA binding activity. MNCs from healthy subjects were cultured to investigate the direct effects of PARP-1 on NF-κB DNA binding activity and the expression of TNF-α and IL-6.
PARP activity and PARP-1 expression in circulating MNCs were increased and positively correlated with plasma TNF-α and IL-6, respectively, in UA patients. Spontaneous NF-κB activation in MNCs was demonstrated in UA patients. In cultured MNCs from healthy subjects, inhibition of PARP-1 prevented lipopolysaccharide-induced increase in DNA binding activity of NF-κB and the expression of TNF-α and IL-6. Supershift assay demonstrated that PARP-1 was a component of NF-κB/DNA complex. Addition of recombinant human PARP-1 protein to nuclear extracts of MNCs significantly increased the DNA binding activity of NF-κB.
Activation and overexpression of PARP-1 are demonstrated in circulating MNCs of UA patients. Overexpressed PARP-1 promotes PARP-1/NF-κB/DNA complex formation, thereby enhancing the expression of TNF-α and IL-6 in circulating MNCs of UA patients.
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Citation Excerpt :
The TNF-α/IL-10 balance may play an important role in various diseases [24]. Elevated plasma TNF-α/IL-4 ratio was associated with greater proinflammatory activity of circulating monocytes during acute myocardial infarction [25] and implied in the pathophysiology of bipolar disorder [26]. Given the potentially important role of a shift in the balance between pro- and anti-inflammatory cytokines toward the former in different somatic (including cardiovascular) and psychiatric diseases, we also computed the ratio between TNF-α and IL-4 and between TNF-α and IL-10.
The burnout syndrome has been associated with an increased risk of cardiovascular disease. The physiological mechanisms potentially involved in this link are underexplored. Knowing that a chronic low-grade systemic inflammatory state contributes to atherosclerosis, we investigated circulating cytokine levels in relation to burnout symptoms.
We studied 167 schoolteachers (median, 48 years; range, 23–63 years; 67% women) who completed the Maslach Burnout Inventory with its three subscales emotional exhaustion (EE), lack of accomplishment (LA), and depersonalization (DP). Levels of the proinflammatory cytokine tumor necrosis factor (TNF)-α and of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 were determined in fasting morning plasma samples. The TNF-α/IL-4 ratio and the TNF-α/IL-10 ratio were computed as two indices of increased inflammatory activity. Analyses were adjusted for demographic factors, medication, lifestyle factors (including sleep quality), metabolic factors, and symptoms of depression and anxiety.
Higher levels of total burnout symptoms aggregating the EE, LA, and DP subscales independently predicted higher TNF-α levels (ΔR²=.024, P=.046), lower IL-4 levels (ΔR²=.021, P=.061), and a higher TNF-α/IL-4 ratio (ΔR²=.040, P=.008). Higher levels of LA predicted decreased IL-4 levels (ΔR²=.041, P=.008) and a higher TNF-α/IL-4 ratio (ΔR²=.041, P=.007). The categorical dimensions of the various burnout scales (e.g., burnout yes vs. no) showed no independent relationship with any cytokine measure.
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^☆: This study was supported by the NNSF of China 30340053, 30400175.

¹: Contributes equally as first author.

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Letter to the EditorAcute myocardial infarction induced increases in plasma tumor necrosis factor-α and interleukin-10 are associated with the activation of poly(ADP-ribose) polymerase of circulating mononuclear cell☆

Abstract

J Biol Chem

J Biol Chem

Letter to the Editor
Acute myocardial infarction induced increases in plasma tumor necrosis factor-α and interleukin-10 are associated with the activation of poly(ADP-ribose) polymerase of circulating mononuclear cell☆