Sungha Park

RAGE signaling in inflammation and arterial aging.

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor (PRR) that interacts with diverse endogenous ligands. Ligation of RAGE triggers a series of cellular signaling events, including the activation of transcription factor NF-kappaB, leading to the production of pro-inflammatory cytokines, and causing inflammation. While acute inflammation serves to resolve pathogen infection and stresses, which promote tissue repair, persistent inflammation results in maladaptive tissue remodeling and damage. RAGE signaling has been implicated in multiple detrimental human illnesses including diabetes, atherosclerosis, arthritis, and Alzheimers disease. In addition, prolonged inflammation often serves as the precursor for arterial remodeling that underlies the exponential increase of age-associated arterial diseases. Despite the significant progress and exciting discoveries in RAGE research, little is known on the biochemistry of RAGE and the signaling mechanism of RAGE remains poorly defined. The biological impact of RAGE signaling in clinical situations and aging-associated diseases also remains to be fully realized. This review attempts to provide a comprehensive summary on both recent findings and missing pieces of the RAGE puzzle.

Sex Differences in Central Hemodynamics and Their Relationship to Left Ventricular Diastolic Function

OBJECTIVES This study aimed to investigate sex differences in the association between arterial stiffness and left ventricular (LV) diastolic dysfunction. BACKGROUND Heart failure with preserved ejection fraction is more common in women. Arterial stiffness has been suggested as a significant contributor to the development of heart failure. We hypothesized that the association between arterial stiffness and LV diastolic function would be stronger in women than in men. METHODS Two-dimensional, Doppler echocardiography and radial artery tonometry were performed simultaneously in 158 age-matched subjects (79 males, 79 females; mean age: 58 ± 10 years) without any structural heart disease or LV systolic dysfunction. RESULTS The peripheral blood pressure and pulse pressure (PP) were similar between sexes. However, central PP and augmentation index were significantly higher and PP amplification was significantly lower in women (1.31 vs. 1.19, p < 0.001). The associations of PP amplification with early diastolic mitral annular (Em) velocity and transmitral to mitral annular early diastolic velocity ratio (E/Em) were significant in women (r = 0.38, p = 0.001; r = -0.36, p = 0.001), whereas no significant association was found in men (r = 0.09, p = 0.428, r = -0.14, p = 0.215). Multiple regression analysis revealed that PP amplification had an independent correlation with Em velocity only in women. CONCLUSIONS Despite similar peripheral PP, the central hemodynamics reflecting arterial stiffness were different between men and women. LV diastolic function correlates significantly with the parameters representing arterial stiffness only in women. We suggest that the effects of earlier wave reflection on central pressure may contribute to greater susceptibility to heart failure with preserved LV ejection fraction in women.

Immunosenescent CD8 + T Cells and C-X-C Chemokine Receptor Type 3 Chemokines Are Increased in Human Hypertension

The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell–driven inflammation in human hypertension has not been confirmed. Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by &ggr; interferon (IFN), IFN &ggr;–induced protein 10, and IFN-inducible T-cell &agr; chemoattractant, in patients with hypertension and in age- and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell &agr; chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8+ T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell &agr; chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell–driven inflammation in hypertension. A more detailed characterization of CD8+ T cells may offer new opportunities for the prevention and treatment of human hypertension.

Role of Inflammation in the Pathogenesis of Arterial Stiffness

Increased arterial stiffness is an independent predictor of cardiovascular disease independent from blood pressure. Recent studies have shed new light on the importance of inflammation on the pathogenesis of arterial stiffness. Arterial stiffness is associated with the increased activity of angiotensin II, which results in increased NADPH oxidase activity, reduced NO bioavailability and increased production of reactive oxygen species. Angiotensin II signaling activates matrix metalloproteinases (MMPs) which degrade TGFβ precursors to produce active TGFβ, which then results in increased arterial fibrosis. Angiotensin II signaling also activates cytokines, including monocyte chemoattractant protein-1, TNF-α, interleukin-1, interleukin-17 and interleukin-6. There is also ample clinical evidence that demonstrates the association of inflammation with increased arterial stiffness. Recent studies have shown that reductions in inflammation can reduce arterial stiffness. In patients with rheumatoid arthritis, increased aortic pulse wave velocity in patients was significantly reduced by anti tumor necrosis factor-α therapy. Among the major classes of anti hypertensive drugs, drugs that block the activation of the RAS system may be more effective in reducing the progression of arterial stiffness. Thus, there is rationale for targeting specific inflammatory pathways involved in arterial stiffness in the development of future drugs. Understanding the role of inflammation in the pathogenesis of arterial stiffness is important to understanding the complex puzzle that is the pathophysiology of arterial stiffening and may be important for future development of novel treatments.

Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays

BackgroundLipid metabolites and cytokines, including chemokines and growth factors, are the key regulators of immune cell function and differentiation, and thus, dysregulation of these regulators is associated with various human diseases. However, previous studies demonstrating a positive correlation of cytokine levels with aging may have been influenced by various environmental factors and underlying diseases. Also, data regarding cytokine profiling in the elderly are limited to a small subset of cytokines.MethodsWe compared the profiles of 22 cytokines, including chemokines and growth factors, in a case-controlled study group of a gender-matched, healthy cohort of 55 patients over the age of 65 and 55 patients under the age of 45. Assessment of serum cytokine concentrations was performed using commercially-available multiplex bead-based sandwich immunoassays.ResultsSoluble CD40 ligand (sCD40L) and transforming growth factor alpha (TGF-α) levels were significantly higher in the elderly patients, whereas granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 (MCP-1) levels were significantly lower in the elderly patients. The partial correlation analysis demonstrating the correlation between cytokine levels when controlled for gender, systolic blood pressure, total cholesterol, HDL cholesterol, triglyceride, and serum creatinine levels further demonstrated that G-CSF, GM-CSF, and MCP-1 had significant negative correlations with age, whereas sCD40L and TGF-α had significant positive correlations.ConclusionsFuture studies will focus on examining the significance of these age-related changes in circulating cytokines and other biological markers and their potential contribution to the development of different age-associated diseases.

Tissue Transglutaminase Is Essential for Integrin-Mediated Survival of Bone Marrow-Derived Mesenchymal Stem Cells

Autologous mesenchymal stem cell (MSC) transplantation therapy for repair of myocardial injury has inherent limitations due to the poor viability of the stem cells after cell transplantation. Adhesion is a prerequisite for cell survival and also a key factor for the differentiation of MSCs. As a novel prosurvival modification strategy, we genetically engineered MSCs to overexpress tissue transglutaminase (tTG), with intention to enhance adhesion and ultimately cell survival after implantation. tTG‐transfected MSCs (tTG‐MSCs) showed a 2.7‐fold and greater than a twofold increase of tTG expression and surface tTG activity, respectively, leading to a 20% increased adhesion of MSCs on fibronectin (Fn). Spreading and migration of tTG‐MSCs were increased 4.75% and 2.52%, respectively. Adhesion of tTG‐MSCs on cardiogel, a cardiac fibroblast‐derived three‐dimensional matrix, showed a 33.1% increase. Downregulation of tTG by transfection of small interfering RNA specific to the tTG resulted in markedly decreased adhesion and spread of MSCs on Fn or cardiogel. tTG‐MSCs on Fn significantly increased phosphorylation of focal adhesion related kinases FAK, Src, and PI3K. tTG‐MSCs showed significant retention in infarcted myocardium by forming a focal adhesion complex and developed into cardiac myocyte‐like cells by the expression of cardiac‐specific proteins. Transplantation of 1 × 106 MSCs transduced with tTG into the ischemic rat myocardium restored normalized systolic and diastolic cardiac function. tTG‐MSCs further restored cardiac function of infarcted myocardium as compared with MSC transplantation alone. These findings suggested that tTG may play an important role in integrin‐mediated adhesion of MSCs in implanted tissues.

Endovascular therapy combined with immunosuppressive treatment for occlusive arterial disease in patients with Takayasu's arteritis.

Purpose: To evaluate the feasibility and efficacy of endovascular therapy combined with immunosuppression for the treatment of arterial occlusive disease in patients with Takayasus arteritis (TA). Methods: From January 1998 to June 2003, 25 patients (22 women; age 37.8±15.5 years) with TA were treated with angioplasty for symptomatic lesions or with a hemodynamically significant aortic narrowing. The patients with active disease, defined as an increase in inflammatory markers (e.g., erythrocyte sedimentation rate [ESR]), were treated with immunosuppressive agents before intervention. Angioplasty was performed after the ESR had been normalized. Results: In the 25 patients, 58 vascular territories (7 aortic, 9 carotid, 3 vertebral, 11 subclavian, 2 superior mesenteric, 18 renal, 4 iliac, and 4 coronary arteries) were treated with angioplasty only (19 lesions) or with stents (39 lesions). The mean ESR when the vascular lesions were initially diagnosed was 35.6±26.2 mm/h, which fell to 18.5±7.8 mm/h after immunosuppressive therapy. The endovascular procedure was performed successfully in 52 (90%) of 58 lesions. During the mean 23.7±18.4-month follow-up, 9 (17%) treated segments restenosed; 4 were treated with repeat angioplasty. The overall cumulative primary clinical success rate was 82%; secondary clinical success was 90%. Conclusions: Endovascular therapy for stenotic lesions in patients with TA is safe and effective when disease activity is strictly controlled with immunosuppressive treatment.

Role of vascular smooth muscle cell in the inflammation of atherosclerosis

Atherosclerosis is a pathologic process occurring within the artery, in which many cell types, including T cell, macrophages, endothelial cells, and smooth muscle cells, interact, and cause chronic inflammation, in response to various inner- or outer-cellular stimuli. Atherosclerosis is characterized by a complex interaction of inflammation, lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix remodeling, which will result in the formation of an intimal plaque. Although the regulation and function of vascular smooth muscle cells are important in the progression of atherosclerosis, the roles of smooth muscle cells in regulating vascular inflammation are rarely focused upon, compared to those of endothelial cells or inflammatory cells. Therefore, in this review, we will discuss here how smooth muscle cells contribute or regulate the inflammatory reaction in the progression of atherosclerosis, especially in the context of the activation of various membrane receptors, and how they may regulate vascular inflammation. [BMB Reports 2014; 47(1): 1-7]

RAGE and cardiovascular disease.

RAGE is pattern recognizing receptors for diverse endogenous ligands. RAGE activation by RAGE ligands is known to be associated with reactive oxygen species generation, activation of NF kappa B, as well as recruitment of proinflammatory cells. Activated endothelial cells, vascular smooth muscle cells in atherosclerotic plaques and activated inflammatory cells all have increased expression of RAGE, which with its interaction with RAGE ligands increases the secretion of proinflammatory cytokines and cell adhesion molecules. Furthermore, RAGE may have a significant role in leukocyte recruitment into the intima of the atherosclerosis. Initial insults resulting in endothelial dysfunction will result in leukocyte infiltration, oxidative stress and vascular inflammation that is amplified by RAGE activation. RAGE and its interaction with RAGE ligands may be important for initializing and maintaining the pathological processes that result in various entities of cardiovascular disease. Soluble RAGE competitively inhibits the binding of RAGE ligands to RAGE and attenuates the development of atherosclerosis in vivo. Thus RAGE may be a promising target for treatment of cardiovascular disease in the future.

Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and proinflammatory ligand for RAGE (EN-RAGE) are associated with carotid atherosclerosis in patients with peritoneal dialysis.

OBJECTIVES The soluble receptor for advanced glycation end products (sRAGE) exerts a protective effect on the development of atherosclerotic vascular complications by inhibiting RAGE-mediated inflammatory response. In contrast, extracellular newly identified RAGE-binding protein (EN-RAGE) contributes to increased atherosclerosis as a pro-inflammatory ligand for RAGE. We determined the levels of sRAGE and EN-RAGE in peritoneal dialysis (PD) patients and evaluated their relationship with carotid atherosclerosis. METHODS A cross-sectional study was performed in 91 PD patients and 29 control subjects. Carotid IMT (cIMT) and abdominal aortic vascular calcification score (VCS) were evaluated using high-resolution B-mode ultrasonography and plain radiographic film of the lateral abdomen. RESULTS Plasma sRAGE and EN-RAGE levels were more than twice as higher in PD patients compared to controls. EN-RAGE showed a strong positive correlation with serum high-sensitivity CRP (p=0.007) and IL-6 (p=0.002), whereas sRAGE was negatively associated with those inflammatory markers (p=0.001, p=0.031). Even after adjustments for traditional cardiovascular risk factors, both sRAGE and EN-RAGE were independently associated with cIMT (β=-0.230, p=0.037, β=0.155, p=0.045) and VCS (β=-0.205, p=0.049, β=0.197, p=0.156). Multivariate logistic analysis revealed that old age (OR 1.14, 95% CI 1.03-1.25, p=0.009), presence of diabetes (OR 13.4, 95% CI: 1.20-150.18, p=0.035) and elevated plasma EN-RAGE (OR 2.26, 95% CI: 1.05-5.11, p=0.048) were significant predictors for the occurrence of carotid atherosclerosis (cIMT>1.0mm and/or plaque formation). CONCLUSIONS Our findings suggest that elevated plasma EN-RAGE and decreased sRAGE level could play a crucial role in systemic inflammation and carotid atherosclerosis in PD patients.