Eplerenone Reverses Cardiac Fibrosis via the Suppression of Tregs by Inhibition of Kv1.3 Channel

Shao, Pei-Pei; Liu, Changjiang; Xu, Quangang; Zhang, Bo; Li, Shaohua; Wu, Yang; Sun, Zhan; Cheng, Lufeng

doi:10.3389/fphys.2018.00899

Cited by 20 publications

(12 citation statements)

References 34 publications

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“…Shao et al showed that MR modulates the activation of Treg cells in congestive heart failure. 106 Advanced congestive heart failure activates Treg cell proliferation via the upregulation of Kv1.3 K + channel, which promotes cardiac fibrosis by stimulating secretion of TGF-β. Coincubation of cardiac fibroblasts with Treg cells increased proliferation and levels of collagen I, III, and matrix metalloproteinase (MMP)-2.…”

Section: Aldosterone and Adaptive Immunitymentioning

confidence: 99%

Aldosterone, Inflammation, Immune System, and Hypertension

Ferreira

Tostes

Paradis

et al. 2020

American Journal of Hypertension

156

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Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress and other manifestations of end-organ damage, that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates pro-inflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome and heart failure.

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Section: Aldosterone and Adaptive Immunitymentioning

confidence: 99%

Aldosterone, Inflammation, Immune System, and Hypertension

Ferreira

Tostes

Paradis

et al. 2020

American Journal of Hypertension

156

View full text Add to dashboard Cite

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“…Similarly to their helper CD4 + counterpart, human T reg s also have a high number of voltage-gated K V 1.3 channels ( Estes et al, 2008 ; Shao et al, 2018 ) and a low number of K Ca 3.1 channels in their membrane ( Varga et al, 2009 ). Intratumoral T reg s have a peculiar T-cell receptor repertoire whose stimulation may have an important role in their immunosuppressive function ( Ahmadzadeh et al, 2019 ).…”

Section: Immunity and Pdacmentioning

confidence: 99%

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

et al. 2021

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Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the “hallmarks of cancer.” Their expression is dysregulated in cancer, and they are “misused” to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same “profibrotic” ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

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“…Comparative expression analysis revealed that Tregs of MS patients express fewer Kv1.3 channels than naive cells, while this difference was not found in healthy donors [43]. Accordingly, modulation of Kv1.3 supports a protective channel function: upregulation resulted in boosted Treg proliferation, and experiments with the high-affinity Kv1.3 antagonist eplerenone revealed diminished TGF-β and IL-10 secretion in treated Tregs [44]. Furthermore, inhibition of Kv1.3 in human lymphocytes led to decreased Ca 2+ entry with larger defects monitored in CD4 + than CD8 + T cells [45].…”

Section: Crac Channelsmentioning

confidence: 91%

Impact of Diverse Ion Channels on Regulatory T Cell Functions

Vinnenberg

Böck

Hundehege

et al. 2021

Cell Physiol Biochem

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The population of regulatory T cells (Tregs) is critical for immunological self-tolerance and homeostasis. Proper ion regulation contributes to Treg lineage identity, regulation, and effector function. Identified ion channels include Ca2+ release-activated Ca2+, transient receptor potential, P2X, volume-regulated anion and K+ channels Kv1.3 and KCa3.1. Ion channel modulation represents a promising therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This review summarizes studies with gene-targeted mice and pharmacological modulators affecting Treg number and function. Furthermore, participation of ion channels is illustrated and the power of future research possibilities is discussed.

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Eplerenone Reverses Cardiac Fibrosis via the Suppression of Tregs by Inhibition of Kv1.3 Channel

Cited by 20 publications

References 34 publications

Aldosterone, Inflammation, Immune System, and Hypertension

Aldosterone, Inflammation, Immune System, and Hypertension

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

Impact of Diverse Ion Channels on Regulatory T Cell Functions

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