Myocardial gene expression of inflammatory cytokines after heart transplantation in relation to the development of transplant coronary artery disease

doi:10.1016/S0002-9149(03)00836-1

The American Journal of Cardiology

Volume 92, Issue 6, 15 September 2003, Pages 715-717

https://doi.org/10.1016/S0002-9149(03)00836-1 Get rights and content

Abstract

Long-term success of cardiac transplantation is mainly limited by the development of transplant coronary artery disease (CAD); it is generally accepted that it is immune mediated, involving cytokines and growth factors. We show that development of transplant CAD is associated with a particular cytokine profile in myocardial biopsies characterized by a late (i.e., 1 year) increase in tumor necrosis factor-α and interferon-γ gene expression, which precede and potentially contribute to the development of allograft vasculopathy, further supporting a role for inflammation and the pathogenesis of transplant CAD in humans.

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Cited by (14)

TNF-alpha-308G>A polymorphism and the risk of familial CAD in a Pakistani population
2015, Human Immunology
Citation Excerpt :
Earlier reports have shown an association of high TNF-alpha concentrations with increased risk of CAD [20,21]. Likewise, higher levels of TNF-alpha have been significantly associated with advanced heart failure and post-transplant CAD [22,23]. Hence, our findings of increased TNF-alpha levels from affected subjects with CAD are in agreement with the reports on case–control CAD cohorts with elevated TNF-alpha levels [24].
A case–control and trio-families study was performed to establish a potential association between TNF-alpha gene promoter SNPs at -308 and -238, and occurrence of CAD in a Pakistani population. In the first phase, 150 patients and 150 controls were enrolled in the case–control association study. In the second phase, heritability of susceptible alleles was investigated from 88 trio-families with CAD affected offspring. Biochemical analysis of lipids and hs-CRP was carried out spectrophotometrically, while serum TNF-alpha concentrations were determined by enzyme-linked immunosorbent assay. Genotyping of the TNF-alpha SNPs were determined by PCR-RFLP method. Elevated serum TNF-alpha and hs-CRP were observed from CAD vs. controls (P < 0.0001; for both). The evaluation of TNF-alpha-308G>A polymorphism in case–control study revealed that the said SNP was significantly associated with the increased risk of CAD. The findings demonstrated a significant link between the TNF-alpha variant allele A at -308 and CAD (P = 0.0035), whereas the -238 SNP was not associated with the disease. Haplotype A–G of the TNF-alpha gene at -308G>A and -238G>A showed higher frequency in the patient group compared with controls (P < 0.05). Moreover, data showed preferential transmission of the disease susceptible allele A at TNF-alpha-308 from parent to affected offspring in a trio-family study (P < 0.0001). The current research leads to conclusion that the TNF-alpha-308G>A polymorphism is associated with CAD in the study population. Furthermore, for the first time, we showed that the TNF-alpha-308A allele was significantly associated with the familial CAD in our high risk population.
Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly
2006, Mechanisms of Ageing and Development
Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-α, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.
Peripheral expansion of circulating T-helper 1 cells predicts coronary endothelial dysfunction after cardiac transplantation
2005, Journal of Heart and Lung Transplantation
We sought to assess the importance of Th1 cells for the development of cardiac allograft vasculopathy.
Despite improvements in immunosuppressive regimens, chronic rejection still represents one of the leading causes of death beyond the first year after heart transplantation. Chronic rejection is characterized by the development of transplant vasculopathy. The exact mechanisms initiating and promoting this form of arteriosclerosis in the human setting remain unclear.
In order to assess the role of T lymphocytes we characterized differentiated T-cell subsets in 32 transplant recipients early after transplantation using RT-PCR, flow cytometry and immunhistochemistry and matched these findings with endothelial function testing as an early clinical indicator of transplant vasculopathy.
Allograft endothelial dysfunction (ED) was defined as a compromised coronary flow reserve to acetylcholine (CFVR < 2 in 8 of 32 transplant recipients). In these patients, mRNA transcript levels for the T-helper (Th)1 signature cytokines interferon (INF)-γ (p < 0.0001) and interleukin (IL)-2 (p < 0.005) and STAT4 (Th1 transcription factor, p < 0,05) were significantly higher than in the remaining 24 patients with normal endothelial function. This correlated with a significant increase in circulating CD3⁺/IFN-γ⁺-T-cells (28.6 ± 4.4% vs 8.7 ± 5.6%; p < 0.0001). In contrast, transcript levels for the Th2 signature cytokines (IL-4, IL-10) and STAT6 (Th2 transcription factor) did not differ significantly between the two groups.
Peripheral expansion of circulating Th1 but not Th2 cells predicts coronary ED after cardiac transplantation. Therefore, quantification of circulating T cells might be a diagnostic tool to predict development of ED in patients after heart transplantation.
Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages
2005, Journal of Biological Chemistry
Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Proinflammatory cytokines such as interferon-γ (IFN-γ), lipopolysaccharide (LPS), or tumor necrosis factor-α can promote macrophage activation. Conversely, anti-inflammatory factors such as transforming growth factor-β1 (TGF-β1) can decrease proinflammatory activation. The molecular mediators regulating the balance of these opposing effectors remain incompletely understood. Herein, we identify Kruppel-like factor 4 (KLF4) as being markedly induced in response to IFN-γ, LPS, or tumor necrosis factor-α and decreased by TGF-β1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker inducible nitric-oxide synthase and inhibited the TGF-β1 and Smad3 target gene plasminogen activator inhibitor-1 (PAI-1). Conversely, KLF4 knockdown markedly attenuated the ability of IFN-γ, LPS, or IFN-γ plus LPS to induce the iNOS promoter, whereas it augmented macrophage responsiveness to TGF-β1 and Smad3 signaling. The KLF4 induction of the iNOS promoter is mediated by two KLF DNA-binding sites at –95 and –212 bp, and mutation of these sites diminished induction by IFN-γ and LPS. We further provide evidence that KLF4 interacts with the NF-κB family member p65 (RelA) to cooperatively induce the iNOS promoter. In contrast, KLF4 inhibited the TGF-β1/Smad3 induction of the PAI-1 promoter independent of KLF4 DNA binding through a novel antagonistic competition with Smad3 for the C terminus of the coactivator p300/CBP. These findings support an important role for KLF4 as a regulator of key signaling pathways that control macrophage activation.
N-octanoyl dopamine attenuates the development of transplant vasculopathy in rat aortic allografts via smooth muscle cell protective mechanisms
2016, Transplantation
Cytokine pro file in heart transplantation
2013, Inflammatory Response in Cardiovascular Surgery

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Myocardial gene expression of inflammatory cytokines after heart transplantation in relation to the development of transplant coronary artery disease

Abstract

Am J Cardiol

J Am Coll Cardiol

Am J Pathol

A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejectionHeart Rejection Study Group. The International Society for Heart Transplantation

J Heart Transplant

Clinical and virological monitoring of human cytomegalovirus infection in 294 heart transplant recipients

Transplantation

Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure

Cardiovasc Res