Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

Sampson, Natalie; Berger, Peter; Zenzmaier, Christoph

doi:10.1155/2012/458276

Cited by 53 publications

(66 citation statements)

References 148 publications

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“…Inhibition of the activation of the primary effector cells of fibrosis appears to be a central mechanism of the observed antifibrotic properties of sGC stimulators and activators and is in line with data obtained after enhancement of the NO/cGMP signaling pathways by NO donors or PDE5 inhibitors [1,3] .…”

Section: Inhibition and Reversal Of Tgfβ-induced Myofibroblast Differsupporting

confidence: 86%

“…Aging is considered a risk factor for fibrosis and the incidence increases sharply with advancing age for many fibrosis-associated diseases, e.g. cardiovascular disease and arteriosclerosis, hepatic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and benign prostatic hyperplasia [3] . The molecular mechanisms underlying these age-related differences in disease incidence are not well understood.…”

Section: Fibrosis and Agingmentioning

confidence: 99%

“…The molecular mechanisms underlying these age-related differences in disease incidence are not well understood. However, several age-related factors have been proposed, including accumulation of cellular or molecular damage, impaired stress response, cellular senescence, dysregulation of telomere biology, loss of proteostasis, and epigenetic alterations [3,4] .…”

Section: Fibrosis and Agingmentioning

confidence: 99%

“…Myofibroblasts have a contractile phenotype and, in contrast to fibroblasts, express smooth muscle cell-specific proteins such as α-smooth muscle cell actin (SMA) or calponin (CNN), which therefore serve as myofibroblast markers [1,3,12] .…”

Section: Inhibition and Reversal Of Tgfβ-induced Myofibroblast Differmentioning

confidence: 99%

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The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review

2016

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Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-β signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis. Increases in NO/cGMP can lead to relaxation of smooth muscle cells triggering vasorelaxation. In addition, there is consistent evidence from preclinical in vitro and in vivo models that increased cGMP also exerts antifibrotic effects. However, most of these findings are descriptive and the molecular pathways are still being investigated. Furthermore, in a variety of fibrotic diseases and also during the natural course of aging, NO/cGMP production is low, and current treatment approaches to increase cGMP levels might not be sufficient. The introduction of compounds that specifically target and stimulate soluble guanylate cyclase (sGC), the so called sGC stimulators and sGC activators, might be able to overcome these limitations and could be ideal tools for investigating antifibrotic mechanisms in vitro and in vivo as they may provide effective treatment strategies for fibrotic diseases. These drugs increase cGMP independently from NO via direct modulation of sGC activity, and have synergistic and additive effects to endogenous NO. This review article describes the NO/cGMP signaling pathway and its involvement in fibrotic remodeling. The classes of sGC modulator drugs and their mode of action are described. Finally, the preclinical in vitro and in vivo findings and antifibrotic effects of cGMP elevation via sGC modulation are reviewed. sGC stimulators and activators significantly attenuate tissue fibrosis in a variety of internal organs and in the skin. Moreover, these compounds seem to have multiple intervention sites and may reduce extracellular matrix formation, fibroblast proliferation, and myofibroblast activation. Thus, sGC stimulators and sGC activators may offer an efficacious and tolerable therapy for fibrotic diseases, and clinical trials are currently underway to assess the potential benefit for patients with systemic sclerosis.

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Section: Inhibition and Reversal Of Tgfβ-induced Myofibroblast Differsupporting

confidence: 86%

Section: Fibrosis and Agingmentioning

confidence: 99%

Section: Fibrosis and Agingmentioning

confidence: 99%

Section: Inhibition and Reversal Of Tgfβ-induced Myofibroblast Differmentioning

confidence: 99%

See 2 more Smart Citations

The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review

2016

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“…7). Although the source of ROS remains uncertain, protein phosphatase inactivation via thiol oxidation by ROS has been proposed as the mechanism for PDGFR autophosphorylation (22,33). Intriguingly, a recent study demonstrated that ROS may indirectly phosphorylate PDGFR through Src family kinases activation in the absence of PDGF (11).…”

Section: Discussionmentioning

confidence: 99%

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Kobayashi

Araya

Minagawa

et al. 2016

The Journal of Immunology

116

117

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Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

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Nitric Oxide‐Based Nanomedicines for Conquering TME Fortress: Say “NO” to Insufficient Tumor Treatment

Xiang,

Chen,

Nan

et al. 2023

Adv Funct Materials

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Almost all cancer treatments are significantly limited by the strong tumor microenvironment (TME) fortress formed by abnormal vasculature, dense extracellular matrix (ECM), multidrug resistance (MDR) system, and immune “cold” environment. In the huge efforts of dismantling the TME fortress, nitric oxide (NO)‐based nanomedicines are increasingly occupying a central position and have already been identified as super “strong polygonal warriors” to dismantle TME fortress for efficient cancer treatment, benefiting from NO's unique physicochemical properties and extremely fascinating biological effects. However, there is a paucity of systematic review to elaborate on the progress and fundamental mechanism of NO‐based nanomedicines in oncology from this aspect. Herein, the key characteristics of TME fortress and the potential of NO in reprogramming TME are delineated and highlighted. The evolution of NO donors and the advantages of NO‐based nanomedicines are discussed subsequently. Moreover, the latest progress of NO‐based nanomedicines for solid tumors is comprehensively reviewed, including normalizing tumor vasculature, overcoming ECM barrier, reversing MDR, and reactivating the immunosuppression TME. Lastly, the prospects, limitations, and future directions on NO‐based nanomedicines for TME manipulation are discussed to provide new insights into the construction of more applicable anticancer nanomedicines.

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Therapeutic Targeting of Redox Signaling in Myofibroblast Differentiation and Age-Related Fibrotic Disease

Cited by 53 publications

References 148 publications

The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review

The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Nitric Oxide‐Based Nanomedicines for Conquering TME Fortress: Say “NO” to Insufficient Tumor Treatment

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