Pro-inflammatory cytokines and endothelium-dependent vasodilation in the forearm. Serial assessment in patients with congestive heart failure

Abstract Background Cardiovascular diseases, including heart failure, are the most common cause of death globally. Recent studies support a high degree of comorbidity between heart failure and cognitive and mood disorders resulting in memory loss, depression, and anxiety. While neuroinflammation in the hypothalamic paraventricular nucleus contributes to autonomic and cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively assess markers of neuroinflammation (glial morphology, cytokines, and A1 astrocyte markers) in the central amygdala, a critical forebrain region involved in emotion and cognition, and to determine its time course and correlation to disease severity during the progression of heart failure. Methods We developed and implemented a comprehensive microglial/astrocyte profiler for precise three-dimensional morphometric analysis of individual microglia and astrocytes in specific brain nuclei at different time points during the progression of heart failure. To this end, we used a well-established ischemic heart failure rat model. Morphometric studies were complemented with quantification of various pro-inflammatory cytokines and A1/A2 astrocyte markers via qPCR. Results We report structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, and glial branches, resulting overall in somatic swelling and deramification, indicative of a change in glial state. These changes occurred in a time-dependent manner, correlated with the severity of heart failure, and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of pro-inflammatory cytokines and markers of reactive A1-type astrocytes in the paraventricular nucleus and central amygdala during heart failure. Conclusion We provide evidence that in addition to the previously described hypothalamic neuroinflammation implicated in sympathohumoral activation during heart failure, microglia, and astrocytes within the central amygdala also undergo structural remodeling indicative of glial shifts towards pro-inflammatory phenotypes. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and potential therapeutic target that could be associated with emotional and cognitive deficits commonly observed at later stages during the course of heart failure.

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Emaciation, Congestive Heart Failure, and Systemic Amyloidosis in Severe Recessive Dystrophic Epidermolysis Bullosa: Possible Internal Complications Due to Skin-Derived Inflammatory Cytokines Derived from the Injured Skin

Dermatopathology ◽

10.3390/dermatopathology7020007 ◽

2020 ◽

Vol 7 (2) ◽

pp. 41-47

Author(s):

Yoshiaki Matsushima ◽

Kento Mizutani ◽

Hiroyuki Goto ◽

Takehisa Nakanishi ◽

Makoto Kondo ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Inflammatory Cytokines ◽

Epidermolysis Bullosa ◽

Systemic Amyloidosis ◽

Epithelial Tissue ◽

Ulcer Formation ◽

Dystrophic Epidermolysis Bullosa ◽

Systemic Complications ◽

Recessive Dystrophic Epidermolysis Bullosa

Inherited epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by epithelial tissue fragility. Recessive dystrophic epidermolysis bullosa (RDEB) is the most severe form, characterized by the presence of blisters, erosion, and ulcer formation, leading to scarring and contraction of the limbs. RDEB is also associated with extra-cutaneous complications, including emaciation, congestive heart failure, and systemic amyloidosis. The main cause of these clinical complications is unknown; however, we hypothesized that they are caused by elevated circulating inflammatory cytokines overproduced by injured keratinocytes. We addressed this phenomenon using keratin-14 driven, caspase-1 overexpressing, transgenic (KCASP1Tg) mice in which injured keratinocytes release high levels of IL-1α and β. KCASP1Tg showed severe spontaneous dermatitis, as well as systemic complications, including aberrant weight loss, cardiovascular disease, and extensive amyloid deposition with organ dysfunction, resembling the complications observed in severe EB. These morbid conditions were partially ameliorated by simultaneous administration of anti-IL-1α and β antibodies. The skin not only constitutes a physical barrier, but also functions as the largest immune organ. We suggest a novel role for IL-1 in the pathogenesis of EB and the use of anti-IL-1 antibodies as a potential therapy for EB complications.

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Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure

Atherosclerosis ◽

10.1016/j.atherosclerosis.2007.09.039 ◽

2008 ◽

Vol 199 (1) ◽

pp. 215-221 ◽

Cited By ~ 34

Author(s):

Kallirrhoe Kourea ◽

John T. Parissis ◽

Dimitrios Farmakis ◽

Fotios Panou ◽

Ioannis Paraskevaidis ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Fas Ligand ◽

Interleukin 10 ◽

Soluble Fas ◽

Darbepoetin Alpha ◽

Anti Inflammatory Cytokine ◽

Pro Inflammatory Cytokines

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Activation of angiotensin II type‐1 receptors stimulates microglial production of pro‐inflammatory cytokines in hypothalamic paraventricular nucleus of heart failure rats

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.697.2 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Yang Yu ◽

Zhi‐Hua Zhang ◽

Shun‐Guang Wei ◽

Robert M Weiss ◽

Robert B Felder

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Inflammatory Cytokines ◽

Paraventricular Nucleus ◽

Hypothalamic Paraventricular Nucleus ◽

Pro Inflammatory Cytokines

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Abstract 13767: Thymosin β4 and its Cleavage Product Ac-SDKP Are Down-regulated in Left Ventricular Myocardium of Dogs with Chronic Heart Failure

Circulation ◽

10.1161/circ.130.suppl_2.13767 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ramesh C Gupta ◽

Mengjun Wang ◽

Kefei Zhang ◽

Vinita Sing-Gupta ◽

Hani N Sabbah

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Inflammatory Cytokines ◽

Protein Level ◽

Interstitial Fibrosis ◽

Capillary Density ◽

Cleavage Product ◽

Thymosin Β4 ◽

Protein Levels ◽

Pro Inflammatory Cytokines

Background: Thymosin β4 (Tβ4) is a 43 amino acid peptide and has been shown to promote angiogenesis, suppress pro-inflammatory cytokines and protect cardiomyocytes from apoptosis and oxidative stress injury. The Tβ4 cleavage product Ac-SDKP is a tetrapeptide (Acetyl-Ser-Asp-Lys-Pro) that has been shown to inhibit collagen production by fibroblasts and collagen deposition in the LV of rats with hypertension or myocardial infarction. In the setting of chronic heart failure (HF), LV dysfunction and chamber remodeling are associated with interstitial fibrosis, reduced capillary density, cardiomyocyte apoptosis and increased production of reactive oxygen species (ROS). Hypothesis: This study tested the hypothesis that protein levels of both Tβ4 and its cleavage product Ac-SDKP are down-regulated in LV myocardium of dogs with advanced chronic HF. Methods: LV tissue was obtained from the LV free wall of 6 normal dogs and 6 dogs with chronic HF (LV ejection fraction ~30%) produced by multiple sequential intracoronary microembolizations. Protein levels of Tβ4 and β-actin, as internal control, were determined by Western blotting and bands expressed in densitometric units (du). Levels of Ac-SDKP were determined by ELISA and expressed in ng/mg protein. Results: Protein level of β-actin did not change significantly between normal dogs (1.34 ± 0.19 du) and dogs with chronic HF (1.22 ± 0.18 du). Protein level of Tβ4 was significantly lower in LV myocardium of dogs with HF compared to normal dogs (0.36 ± 0.06 vs. 1.64 ± 0.13 du, p<0.05). Similarly, levels of Ac-SDKP were significantly lower in LV myocardium of HF dogs compared to normal dogs (93 ± 9 vs. 155 ± 4 ng/mg protein, p<0.05). Conclusions: Protein levels of Tβ4 and its cleavage tetrapeptide Ac-SDKP are markedly down-regulated in LV myocardium dogs with chronic HF. These findings are in-line with the reported increase of pro-inflammatory cytokines, interstitial fibrosis, cardiomyocyte apoptosis, and ROS formation as well as reduced capillary density in the failing LV myocardium of dogs with microembolization-induced HF as well as patients with HF. The findings support the therapeutic targeting of Tβ4 and Ac-SDKP as potential treatment for chronic HF.

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