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Senescent Cells Impair Erectile Function through Induction of Endothelial Dysfunction and Nerve Injury in Mice.

Nishimatsu H, Suzuki E, Saito Y, Niimi A, Nomiya A, Fukuhara H, Kume H, Homma Y - PLoS ONE (2015)

Bottom Line: Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection.These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury.These effects may be mediated by proinflammatory cytokines produced by senescent cells.

View Article: PubMed Central - PubMed

Affiliation: The Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Erectile dysfunction (ED) is a major health problem, particularly in the elderly population, which is rapidly increasing. It is necessary to elucidate the mechanism by which ED occurs in the elderly. Cellular senescence is commonly detected in old tissues, and it is well known that senescent cells not only withdraw from the cell cycle but also remain viable and actively produce a variety of cytokines. We examined the effect of senescent cells on erectile function after injection of senescent cells into the penises of mice. Human umbilical vein endothelial cells were infected with an adenovirus expressing a constitutively active mutant of Ras to induce senescence, and were injected into the penises of nude mice. These senescent cells expressed proinflammatory cytokines such as interleukin-1β (IL-1β). Injection of senescent cells impaired erectile function, as assessed by the measurement of intracavernous pressure. Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection. The penises injected with the senescent cells expressed human IL-1β and subsequently endogenous proinflammatory cytokines such as mouse IL-1β and tumor necrosis factor-α. These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury. These effects may be mediated by proinflammatory cytokines produced by senescent cells.

No MeSH data available.


Related in: MedlinePlus

The expression of proinflammatory cytokines in the penis.AdGFP_HUVECs (AdGFP) and AdRas12V_HUVECs (AdRas12V) were injected in the penises of nude mice and RNA was extracted from the penises 1 (1D), 7 (7D), 14 (14D), and 28 (28D) days after injection for real time PCR analysis. Nontreated mice (Control) were also analyzed. A) The expression of human IL-1β that was produced from injected HUVECs. The ratio of human IL-1β to mouse GAPDH was calculated to demonstrate human IL-1β expression in the penises of nude mice. The expression of human IL-1β in AdRas12V_HUVECs–injected penises on day 1 was calculated as 1.0 and the fold induction was shown in other groups (n = 5 per group). * and **: P<0.05 and P<0.01, respectively vs. AdRas12V_HUVECs–injected penises on day 1, †: P<0.01 vs. AdRas12V_HUVECs–injected penises at each time point. B) The expression of mouse IL-1β, mouse IL-6, and mouse TNF-α in the AdGFP_HUVECs- or AdRas12V_HUVECs-injected penises. The expression of these cytokines in nontreated control mice (Control) was calculated as 1.0 and fold induction was shown in other groups (n = 5 per group). *: P<0.05 vs. Control, †: P<0.05 vs. AdGFP_HUVECs–injected penises at each time point.
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pone.0124129.g006: The expression of proinflammatory cytokines in the penis.AdGFP_HUVECs (AdGFP) and AdRas12V_HUVECs (AdRas12V) were injected in the penises of nude mice and RNA was extracted from the penises 1 (1D), 7 (7D), 14 (14D), and 28 (28D) days after injection for real time PCR analysis. Nontreated mice (Control) were also analyzed. A) The expression of human IL-1β that was produced from injected HUVECs. The ratio of human IL-1β to mouse GAPDH was calculated to demonstrate human IL-1β expression in the penises of nude mice. The expression of human IL-1β in AdRas12V_HUVECs–injected penises on day 1 was calculated as 1.0 and the fold induction was shown in other groups (n = 5 per group). * and **: P<0.05 and P<0.01, respectively vs. AdRas12V_HUVECs–injected penises on day 1, †: P<0.01 vs. AdRas12V_HUVECs–injected penises at each time point. B) The expression of mouse IL-1β, mouse IL-6, and mouse TNF-α in the AdGFP_HUVECs- or AdRas12V_HUVECs-injected penises. The expression of these cytokines in nontreated control mice (Control) was calculated as 1.0 and fold induction was shown in other groups (n = 5 per group). *: P<0.05 vs. Control, †: P<0.05 vs. AdGFP_HUVECs–injected penises at each time point.

Mentions: To analyze how long injected HUVECs remained in the penis and produced proinflammatory cytokines, AdGFP_HUVECs and AdRas12V_HUVECs were injected into the penises of nude mice, and real time PCR analysis was performed. We also analyzed the production of endogenous proinflammatory cytokines. The expression of human IL-1β was below the detectable levels in control nude mice into which HUVECs were not injected. The expression of human IL-1β was maximal in the AdRas12V_HUVECs-injected penis 1 day after injection, and the expression had gradually decreased by 14 days after injection. The expression of human IL-1β had almost disappeared 28 days after injection. The expression of human IL-1β in AdGFP_HUVECs-injected penises was significantly lower than that in AdRas12V_HUVECs-injected penises (Fig 6A). We also analyzed the expression of mouse IL-1β, IL-6, and TNF-α to detect the expression of endogenous proinflammatory cytokines (Fig 6B). The expression of mouse IL-1β in AdRas12V_HUVECs-injected penises did not change significantly compared with that in the control nude mice until 7 days after injection. However, the expression of mouse IL-1β increased significantly in AdRas12V_HUVECs-injected penises compared with that in the control nude mice 14 and 28 days after injection. The expression of mouse IL-1β in AdRas12V_HUVECs-injected penises was also significantly higher than that in AdGFP_HUVECs-injected penises 14 and 28 days after injection. The expression of IL-6 did not change significantly during the time course. The expression of mouse TNF-α was significantly higher in AdRas12V_HUVECs-injected penises than that in the control mice 28 days after injection. These results suggested that, although the production of proinflammatory cytokines from injected HUVECs ceased within 14 days, the production of endogenous proinflammatory cytokines started and maintained inflammation thereafter.


Senescent Cells Impair Erectile Function through Induction of Endothelial Dysfunction and Nerve Injury in Mice.

Nishimatsu H, Suzuki E, Saito Y, Niimi A, Nomiya A, Fukuhara H, Kume H, Homma Y - PLoS ONE (2015)

The expression of proinflammatory cytokines in the penis.AdGFP_HUVECs (AdGFP) and AdRas12V_HUVECs (AdRas12V) were injected in the penises of nude mice and RNA was extracted from the penises 1 (1D), 7 (7D), 14 (14D), and 28 (28D) days after injection for real time PCR analysis. Nontreated mice (Control) were also analyzed. A) The expression of human IL-1β that was produced from injected HUVECs. The ratio of human IL-1β to mouse GAPDH was calculated to demonstrate human IL-1β expression in the penises of nude mice. The expression of human IL-1β in AdRas12V_HUVECs–injected penises on day 1 was calculated as 1.0 and the fold induction was shown in other groups (n = 5 per group). * and **: P<0.05 and P<0.01, respectively vs. AdRas12V_HUVECs–injected penises on day 1, †: P<0.01 vs. AdRas12V_HUVECs–injected penises at each time point. B) The expression of mouse IL-1β, mouse IL-6, and mouse TNF-α in the AdGFP_HUVECs- or AdRas12V_HUVECs-injected penises. The expression of these cytokines in nontreated control mice (Control) was calculated as 1.0 and fold induction was shown in other groups (n = 5 per group). *: P<0.05 vs. Control, †: P<0.05 vs. AdGFP_HUVECs–injected penises at each time point.
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Related In: Results  -  Collection

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pone.0124129.g006: The expression of proinflammatory cytokines in the penis.AdGFP_HUVECs (AdGFP) and AdRas12V_HUVECs (AdRas12V) were injected in the penises of nude mice and RNA was extracted from the penises 1 (1D), 7 (7D), 14 (14D), and 28 (28D) days after injection for real time PCR analysis. Nontreated mice (Control) were also analyzed. A) The expression of human IL-1β that was produced from injected HUVECs. The ratio of human IL-1β to mouse GAPDH was calculated to demonstrate human IL-1β expression in the penises of nude mice. The expression of human IL-1β in AdRas12V_HUVECs–injected penises on day 1 was calculated as 1.0 and the fold induction was shown in other groups (n = 5 per group). * and **: P<0.05 and P<0.01, respectively vs. AdRas12V_HUVECs–injected penises on day 1, †: P<0.01 vs. AdRas12V_HUVECs–injected penises at each time point. B) The expression of mouse IL-1β, mouse IL-6, and mouse TNF-α in the AdGFP_HUVECs- or AdRas12V_HUVECs-injected penises. The expression of these cytokines in nontreated control mice (Control) was calculated as 1.0 and fold induction was shown in other groups (n = 5 per group). *: P<0.05 vs. Control, †: P<0.05 vs. AdGFP_HUVECs–injected penises at each time point.
Mentions: To analyze how long injected HUVECs remained in the penis and produced proinflammatory cytokines, AdGFP_HUVECs and AdRas12V_HUVECs were injected into the penises of nude mice, and real time PCR analysis was performed. We also analyzed the production of endogenous proinflammatory cytokines. The expression of human IL-1β was below the detectable levels in control nude mice into which HUVECs were not injected. The expression of human IL-1β was maximal in the AdRas12V_HUVECs-injected penis 1 day after injection, and the expression had gradually decreased by 14 days after injection. The expression of human IL-1β had almost disappeared 28 days after injection. The expression of human IL-1β in AdGFP_HUVECs-injected penises was significantly lower than that in AdRas12V_HUVECs-injected penises (Fig 6A). We also analyzed the expression of mouse IL-1β, IL-6, and TNF-α to detect the expression of endogenous proinflammatory cytokines (Fig 6B). The expression of mouse IL-1β in AdRas12V_HUVECs-injected penises did not change significantly compared with that in the control nude mice until 7 days after injection. However, the expression of mouse IL-1β increased significantly in AdRas12V_HUVECs-injected penises compared with that in the control nude mice 14 and 28 days after injection. The expression of mouse IL-1β in AdRas12V_HUVECs-injected penises was also significantly higher than that in AdGFP_HUVECs-injected penises 14 and 28 days after injection. The expression of IL-6 did not change significantly during the time course. The expression of mouse TNF-α was significantly higher in AdRas12V_HUVECs-injected penises than that in the control mice 28 days after injection. These results suggested that, although the production of proinflammatory cytokines from injected HUVECs ceased within 14 days, the production of endogenous proinflammatory cytokines started and maintained inflammation thereafter.

Bottom Line: Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection.These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury.These effects may be mediated by proinflammatory cytokines produced by senescent cells.

View Article: PubMed Central - PubMed

Affiliation: The Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

ABSTRACT
Erectile dysfunction (ED) is a major health problem, particularly in the elderly population, which is rapidly increasing. It is necessary to elucidate the mechanism by which ED occurs in the elderly. Cellular senescence is commonly detected in old tissues, and it is well known that senescent cells not only withdraw from the cell cycle but also remain viable and actively produce a variety of cytokines. We examined the effect of senescent cells on erectile function after injection of senescent cells into the penises of mice. Human umbilical vein endothelial cells were infected with an adenovirus expressing a constitutively active mutant of Ras to induce senescence, and were injected into the penises of nude mice. These senescent cells expressed proinflammatory cytokines such as interleukin-1β (IL-1β). Injection of senescent cells impaired erectile function, as assessed by the measurement of intracavernous pressure. Although the structure of the cavernous body did not remarkably change, expression of the catalytically active form of endothelial nitric oxide synthase and that of total neural nitric oxide synthase significantly decreased after injection. The penises injected with the senescent cells expressed human IL-1β and subsequently endogenous proinflammatory cytokines such as mouse IL-1β and tumor necrosis factor-α. These results suggested that senescent cells impaired erectile function through induction of endothelial dysfunction and nerve injury. These effects may be mediated by proinflammatory cytokines produced by senescent cells.

No MeSH data available.


Related in: MedlinePlus