Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie’s Disease

Mateus, Marta; Ilg, Marcus M.; Stebbeds, W.; Christopher, Nim; Muneer, Asıf; Ralph, David; Cellek, Selim

doi:10.1016/j.jsxm.2018.05.003

Cited by 20 publications

(31 citation statements)

References 33 publications

(40 reference statements)

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“…Notably the serum levels of TGF-β1 were similar in all groups irrespective of the perioperative approach after treatment with 8-SPT or 5-HD, suggesting the involvement of both signaling pathways in the release of TGF-β1. Previous studies have linked the adenosine signaling with TGF-β1 status in different contexts 57,58 ; however, further research is needed in order to clarify the relative contribution of mitochondrial KATP channel activity and the different types of adenosine-adenosine receptor in the induction of TGF-β1 in the particular setting.…”

Section: Discussionmentioning

confidence: 99%

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

Tsilimigras

Selemenakis

Vlachou

et al. 2020

Sci Rep

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Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemiareperfusion injury (IRI) in local (i.e. kidney) and distant (i.e. heart) tissue. To investigate perioperative approaches that mitigate IRI-induced tissue damage, Wistar rats underwent suprarenal aortic clamping either alone or in combination with short cycles of ischemic conditioning before and/or after clamping. Serum analysis revealed significant reduction in key biochemical parameters reflecting decreased tissue damage at systemic level and improved renal function in conditioned groups compared to controls (p < 0.05), which was corroborated by histolopathological evaluation. Importantly, the levels of DNA damage, as reflected by the biomarkers 8-oxo-G, γH2AX and pATM were reduced in conditioned versus non-conditioned cases. In this setting, NADPH oxidase, a source of free radicals, decreased in the myocardium of conditioned cases. Of note, administration of 5-HD and 8-SPT blocking key protective signaling routes abrogated the salutary effect of conditioning. To further understand the non-targeted effect of IRI on the heart, it was noted that serum TGF-β1 levels decreased in conditioned groups, whereas this difference was eliminated after 5-HD and 8-SPT administration. Collectively, conditioning strategies reduced both renal and myocardial injury. Additionally, the present study highlights TGF-β1 as an attractive target for manipulation in this context. Abdominal aortic aneurysm (AAA) is a potentially life-threatening entity, relatively common in routine clinical practice 1. Despite the introduction of endovascular aortic aneurysm repair (EVAR) as well as the significant improvements in surgical techniques, grafts, and perioperative care during the last decades, AAA repair still carries a considerable risk of morbidity and mortality 2. One of the main concerns in vascular surgery over the years

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Section: Discussionmentioning

confidence: 99%

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

Tsilimigras

Selemenakis

Vlachou

et al. 2020

Sci Rep

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“…Mateus et al showed that among the four knowns adenosine receptors, ADORA1 and ADORA2B are significantly more prevalent in cells derived from PD plaque than non-PD TA tissues. 88 , 89 …”

Section: Introductionmentioning

confidence: 99%

New insights into the pathogenesis of Peyronie's disease: A narrative review

Krakhotkin¹,

Chernylovskyi²,

Mottrie

et al. 2020

Chronic Diseases and Translational Medicine

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Peyronie’s disease (PD) is a benign, progressive fibrotic disorder characterized by scar or plaques within the tunica albuginea (TA) of the penis. This study provides new insights into the pathogenesis of PD based on data from different studies regarding the roles of cytokines, cell signaling pathways, biochemical mechanisms, genetic factors responsible for fibrogenesis. A growing body of literature has shown that PD is a chronically impaired, localized, wound healing process within the TA and the Smith space. It is caused by the influence of different pathological stimuli, most often the effects of mechanical stress during sexual intercourse in genetically sensitive individuals with unusual anatomical TA features, imbalanced matrix metalloproteinase/tissue inhibitor of metalloproteinase (MMP/TIMP), and suppressed antioxidant systems during chronic inflammation. Other intracellular signal cascades are activated during fibrosis along with low expression levels of their negative regulators and transforming growth factor-β1 signaling. The development of multikinase agents with minimal side effects that can block several signal cell pathways would significantly improve fibrosis in PD tissues by acting on common downstream mediators.

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“…Loughborough, United Kingdom) as described previously [16]. The tissue pieces were incubated in DMEM-F12 (GIBCO, Invitrogen,…”

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confidence: 99%

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

et al. 2019

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Background: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. Objective: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. Design, setting, and participants: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. Results and limitations: The new assay was able to detect transforming growth factor-b1induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. Conclusions: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. Patient summary: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.

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Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie’s Disease

Cited by 20 publications

References 33 publications

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

New insights into the pathogenesis of Peyronie's disease: A narrative review

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

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