Restoration of erectile function by suppression of corporal apoptosis and oxidative stress with losartan in aged rats with erectile dysfunction

Wang, Yichuan; Wang, Yamin; Cong, Rong; Tian, Ye; Chen, Chen; Wang, Yichun; Zhang, Qijie; Zhou, Xiang; Ji, Chengjian; Meng, Xuhui; Song, Ninghong

doi:10.1111/andr.12757

Cited by 12 publications

(8 citation statements)

References 43 publications

(44 reference statements)

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“…The above process depends on the normal function of the endothelial cells and smooth muscle cells (3). Several studies have reported that the phosphorylation of AKT and eNOS in the penis of aged rats is decreased (23,24). In the present study, our results indicated that PI3K/AKT and eNOS/ NO/cGMP pathways were downregulated in the aged rats, and this downregulation was accompanied by endothelial dysfunction.…”

Section: Discussionsupporting

confidence: 64%

“…Fibrosis, resulting from diabetes and nerve damage, is also involved in the pathophysiological process of ED (7,25). The process of fibrosis has also been reported to be involved in aging-related ED (18,23). Fibrosis in penile tissue often involves a decrease in the content of cells, such as smooth muscle cells, an increase in the content of collagen, and the fragment and decrease of elastic fibers (26).…”

Section: Discussionmentioning

confidence: 99%

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Study on the mechanism of aging-related erectile dysfunction based on bioinformatics and experimental verification

Sun¹,

Liu²,

Chen³

et al. 2023

Transl Androl Urol

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Background: The incidence of aging-related erectile dysfunction (ED) remains high in the elderly population, and has attracted the attention of the medical community. However, aging-related ED responds poorly to traditional treatments for ED, and its mechanism has not yet been fully clarified. This study sought to explore the potential mechanisms of aging-related ED based on bioinformatics and experimental verification.Methods: A bioinformatics analysis was performed on data from the Gene Expression Omnibus database related to ED and aging, and the associated differentially expressed genes (DEGs) and signaling pathways were identified. Young and aged rats (n=8 per group) were included in the experimental verification study.Erectile function was detected by electrical stimulation of the cavernous nerve. The corpus cavernosum was collected for the follow-up experiments.Results: A total of 4 hub genes were identified, among which biglycan (BGN) appears to play an important role. The functional enrichment analysis revealed that the extracellular matrix (ECM), especially collagen, related pathways, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway were enriched, which was also confirmed by the animal experiments. Impaired erectile function in aged rats was associated with the downregulation of the PI3K/AKT pathway, endothelial dysfunction, and increased fibrosis in the penis.Conclusions: Erectile function is impaired with aging. The downregulation of the PI3K/AKT pathway, endothelial dysfunction, and increased fibrosis are involved in this process. BGN may be the key gene regulating these changes. Our study extended understandings of the mechanisms of age-related ED and provides new potential treatment ideas.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Study on the mechanism of aging-related erectile dysfunction based on bioinformatics and experimental verification

Sun¹,

Liu²,

Chen³

et al. 2023

Transl Androl Urol

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“…Oxidative stress has been causatively linked to ED pathogenesis resulting from a variety of pathologies, including obesity, type 2 diabetes, and aging [ 37 , 38 , 39 , 40 ]. While the penile vasculature represents a unique circulatory system that is predominantly maintained in a low perfusion (flaccid) state primarily by α-adrenergic-mediated vasoconstriction [ 41 ], studies utilizing endothelial cell culture or arteries of the central circulation may provide insights into molecular functioning that may have potential relevance to ED pathology.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Suppresses Penile NADPH Oxidase Activity to Preserve Erectile Function in Mice Fed a Western Diet

Favor

Pierre

Bivalacqua³

et al. 2021

Biomedicines

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The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive cellular signaling kinase that has been implicated in the excess production of reactive oxygen species (ROS). NADPH oxidase-derived ROS have been implicated in erectile dysfunction pathogenesis. The objective of this study was to determine if mTOR is an activator of NADPH oxidase in the penis and to determine the functional relevance of this pathway in a translationally relevant model of diet-induced erectile dysfunction. Male mice were fed a control diet or a high-fat, high-sucrose Western style diet (WD) for 12 weeks and treated with vehicle or rapamycin for the final 4 weeks of the dietary intervention. Following the intervention, erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, in vivo ROS production was measured in the penis using a microdialysis approach, and relative protein contents from the corpus cavernosum were determined by Western blot. Erectile function was impaired in vehicle treated WD-mice and was preserved in rapamycin treated WD-mice. Penile NADPH oxidase-mediated ROS were elevated in WD-mice and suppressed by rapamycin treatment. Western blot analysis suggests mTOR activation with WD by increased active site phosphorylation of mTOR and p70S6K, and increased expression of NADPH oxidase subunits, all of which were suppressed by rapamycin. These data suggest that mTOR is an upstream mediator of NADPH oxidase in the corpus cavernosum in response to a chronic Western diet, which has an adverse effect on erectile function.

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“…Recently, the etiology of age-related ED has been explored from different perspectives to support future clinical transformation. Wang et al [ 8 ] found that increases in apoptosis, fibrosis, and oxidative stress (OS) occurred in rats with age-related ED and may be the targets of losartan. Bragina et al [ 9 ] found that the renin-angiotensin system (RAS) is involved in age-related ED and that the activity of the ACE-Ang II-AT1 axis in the CC is enhanced, which is positively correlated with fibrosis and inflammation of the CC.…”

Section: Introductionmentioning

confidence: 99%

Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction

Cui

et al. 2022

Oxidative Medicine and Cellular Longevity

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Aging has been deemed the primary factor in erectile dysfunction (ED). Herein, age-related changes in the erectile response and histomorphology were detected, and the relationship between aging and ED was investigated based on gene expression levels. Thirty male Sprague–Dawley (SD) rats were randomly divided into 6 groups, and intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured. Subsequently, the corpus cavernosum (CC) was harvested and prepared for histological examinations of apoptosis, oxidative stress (OS), and fibrosis. Then, the microarray dataset (GSE10804) was analyzed to identify differentially expressed genes (DEGs) in ED progression, and hub genes were selected. In addition, aged CC smooth muscle cells (CCSMCs) were isolated to evaluate the function of the hub gene by siRNA interference, qRT–PCR, immunofluorescence staining, enzyme-linked immunosorbent assay, western blot analysis, CCK-8 assay, EdU staining, and flow cytometry approaches. The ICP/MAP and smooth muscle cell (SMC)/collagen ratios declined with aging, while apoptosis and OS levels increased with aging. The enriched functions and pathways of the DEGs were investigated, and 15 hub genes were identified, among which IGFBP3 was significantly upregulated. The IGFBP3 upregulation was verified in the CC of aging rats. Furthermore, aged CCSMCs were transfected with siRNA to knock down IGFBP3 expression. The viability and proliferation of the CCSMCs increased, while apoptosis, OS, and fibrosis decreased. Our findings demonstrate that the erectile response of SD rats declines in parallel with enhanced CC apoptosis, OS, and fibrosis with aging. Upregulation of IGFBP3 plays an important role; furthermore, downregulation of IGFBP3 improves the viability and proliferation of CCSMCs and alleviates apoptosis, OS, and fibrosis. Thus, IGFBP3 is a potential therapeutic target for age-related ED.

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Restoration of erectile function by suppression of corporal apoptosis and oxidative stress with losartan in aged rats with erectile dysfunction

Cited by 12 publications

References 43 publications

Study on the mechanism of aging-related erectile dysfunction based on bioinformatics and experimental verification

Study on the mechanism of aging-related erectile dysfunction based on bioinformatics and experimental verification

Rapamycin Suppresses Penile NADPH Oxidase Activity to Preserve Erectile Function in Mice Fed a Western Diet

Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction

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