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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

Senescence occurs in the penis of diabetic mice.A) The penises were isolated from STZ-induced diabetic C57BL/6J mice 7 weeks after STZ injection. Frozen penile sections were subjected to SA-β-Gal staining. The penises of age-matched control mice were also used. Scale bars = 50 μmeter. B) Immunohistochemical analysis of the penises isolated from STZ-induced diabetic C57BL/6J mice and age-matched control mice. HP-1γ was stained. Arrows indicate the positively stained area. Scale bars = 50 μmeter. C) Western blot analysis of senescence-associated markers. Proteins were extracted from the penises of STZ-induced diabetic C57BL/6J mice (STZ) 7 weeks after STZ injection. Proteins were also extracted from the penises of age-matched control mice (Control). p53 and p21CIP1 expressions were examined. The arrow indicates the bands corresponding to the size of p21CIP1.
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pone.0124129.g001: Senescence occurs in the penis of diabetic mice.A) The penises were isolated from STZ-induced diabetic C57BL/6J mice 7 weeks after STZ injection. Frozen penile sections were subjected to SA-β-Gal staining. The penises of age-matched control mice were also used. Scale bars = 50 μmeter. B) Immunohistochemical analysis of the penises isolated from STZ-induced diabetic C57BL/6J mice and age-matched control mice. HP-1γ was stained. Arrows indicate the positively stained area. Scale bars = 50 μmeter. C) Western blot analysis of senescence-associated markers. Proteins were extracted from the penises of STZ-induced diabetic C57BL/6J mice (STZ) 7 weeks after STZ injection. Proteins were also extracted from the penises of age-matched control mice (Control). p53 and p21CIP1 expressions were examined. The arrow indicates the bands corresponding to the size of p21CIP1.

Mentions: We first measured the casual blood glucose level of the non-diabetic control C57BL/6J mice and STZ-induced diabetic C57BL/6J mice to confirm that these mice became diabetic (Blood glucose level: control; 165.8±15.5 mg/dL vs. STZ; 364.7±28.3 mg/dL, n = 7 per group, P<0.001). We next examined whether cellular senescence occurs in the cavernous body of diabetic mice. The penis of STZ-induced diabetic C57BL/6J mice was sporadically stained with SA-β-Gal (Fig 1A). The positive area was predominantly located on the surface of the trabeculae of the cavernous body corresponding to the vascular endothelial cells (VECs) and/or vascular smooth muscle cells (VSMCs). SA-β-Gal staining was well correlated with HP-1γ immunostaining [23]. Therefore, we performed HP-1γ staining (Fig 1B). HP-1γ was also sporadically stained on the surface of the trabeculae, corresponding to the area of the endothelium. In accordance with this result, expression of p53 and p21CIP1 remarkably increased in diabetic C57BL/6J mice compared with non-diabetic control mice (Fig 1C). These results suggested that cellular senescence occurs in the cavernous body of diabetic mice.


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)

Senescence occurs in the penis of diabetic mice.A) The penises were isolated from STZ-induced diabetic C57BL/6J mice 7 weeks after STZ injection. Frozen penile sections were subjected to SA-β-Gal staining. The penises of age-matched control mice were also used. Scale bars = 50 μmeter. B) Immunohistochemical analysis of the penises isolated from STZ-induced diabetic C57BL/6J mice and age-matched control mice. HP-1γ was stained. Arrows indicate the positively stained area. Scale bars = 50 μmeter. C) Western blot analysis of senescence-associated markers. Proteins were extracted from the penises of STZ-induced diabetic C57BL/6J mice (STZ) 7 weeks after STZ injection. Proteins were also extracted from the penises of age-matched control mice (Control). p53 and p21CIP1 expressions were examined. The arrow indicates the bands corresponding to the size of p21CIP1.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4404101&req=5

pone.0124129.g001: Senescence occurs in the penis of diabetic mice.A) The penises were isolated from STZ-induced diabetic C57BL/6J mice 7 weeks after STZ injection. Frozen penile sections were subjected to SA-β-Gal staining. The penises of age-matched control mice were also used. Scale bars = 50 μmeter. B) Immunohistochemical analysis of the penises isolated from STZ-induced diabetic C57BL/6J mice and age-matched control mice. HP-1γ was stained. Arrows indicate the positively stained area. Scale bars = 50 μmeter. C) Western blot analysis of senescence-associated markers. Proteins were extracted from the penises of STZ-induced diabetic C57BL/6J mice (STZ) 7 weeks after STZ injection. Proteins were also extracted from the penises of age-matched control mice (Control). p53 and p21CIP1 expressions were examined. The arrow indicates the bands corresponding to the size of p21CIP1.
Mentions: We first measured the casual blood glucose level of the non-diabetic control C57BL/6J mice and STZ-induced diabetic C57BL/6J mice to confirm that these mice became diabetic (Blood glucose level: control; 165.8±15.5 mg/dL vs. STZ; 364.7±28.3 mg/dL, n = 7 per group, P<0.001). We next examined whether cellular senescence occurs in the cavernous body of diabetic mice. The penis of STZ-induced diabetic C57BL/6J mice was sporadically stained with SA-β-Gal (Fig 1A). The positive area was predominantly located on the surface of the trabeculae of the cavernous body corresponding to the vascular endothelial cells (VECs) and/or vascular smooth muscle cells (VSMCs). SA-β-Gal staining was well correlated with HP-1γ immunostaining [23]. Therefore, we performed HP-1γ staining (Fig 1B). HP-1γ was also sporadically stained on the surface of the trabeculae, corresponding to the area of the endothelium. In accordance with this result, expression of p53 and p21CIP1 remarkably increased in diabetic C57BL/6J mice compared with non-diabetic control mice (Fig 1C). These results suggested that cellular senescence occurs in the cavernous body of diabetic mice.

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