Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice

Paul R. Hiebert, Wendy A. Boivin, Thomas Abraham, Sara Pazooki, Hongyan Zhao, David J. Granville

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Apolipoprotein E knockout (apoE-KO) mice have been utilized for decades as a model of atherosclerosis. However, in addition to atherosclerosis, apoE-KO mice develop extensive cutaneous xanthomatosis, accelerated skin aging and frailty when fed a high fat diet. Granzyme B (GrB) is a pro-apoptotic serine protease that has recently been shown to exhibit extracellular proteolytic activity in certain pathologies. In the present study, the role of GrB in skin aging and pathology was assessed using the apoE-KO model of skin aging. Male C57BL/6 wild type and apoE-KO mice were grown for 0, 5, 15 or 30. weeks on either a high fat (21.2% fat, 0.2% cholesterol) or regular chow diet (7% fat). ApoE/GrB double knockout (DKO) mice were also generated and assessed after being fed either diet for 30. weeks. Skin was removed from the mid to lower back and examined for age-related changes such as hair loss, skin thinning and collagen remodeling and disorganization. ApoE-KO mice exhibited signs of frailty, hair graying, hair loss, skin thinning, loss of collagen density and increased skin pathologies featuring collagen remodeling and reduced decorin compared to wild type controls. These phenotypes occurred earlier and were more severe when fed a high fat diet. In addition, we also observed increased GrB expression in proximity to areas of decorin degradation and reduced collagen density in the skin of apoE-KO mice. DKO mice exhibited protection against skin thinning, ECM degradation and loss of dermal collagen density. In summary, our results provide novel insights into the effects of a high fat diet and apoE deficiency on skin aging and pathology and suggest a role for GrB in age-related skin thinning and frailty.

Original languageEnglish (US)
Pages (from-to)489-499
Number of pages11
JournalExperimental Gerontology
Volume46
Issue number6
DOIs
StatePublished - Jun 1 2011

Fingerprint

Skin Aging
Granzymes
Apolipoproteins E
Knockout Mice
Extracellular Matrix
Skin
Aging of materials
Nutrition
Collagen
Fats
Pathology
High Fat Diet
Decorin
Alopecia
Atherosclerosis
Diet
Xanthomatosis
Military electronic countermeasures
Serine Proteases
Degradation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

Cite this

Hiebert, Paul R. ; Boivin, Wendy A. ; Abraham, Thomas ; Pazooki, Sara ; Zhao, Hongyan ; Granville, David J. / Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice. In: Experimental Gerontology. 2011 ; Vol. 46, No. 6. pp. 489-499.
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abstract = "Apolipoprotein E knockout (apoE-KO) mice have been utilized for decades as a model of atherosclerosis. However, in addition to atherosclerosis, apoE-KO mice develop extensive cutaneous xanthomatosis, accelerated skin aging and frailty when fed a high fat diet. Granzyme B (GrB) is a pro-apoptotic serine protease that has recently been shown to exhibit extracellular proteolytic activity in certain pathologies. In the present study, the role of GrB in skin aging and pathology was assessed using the apoE-KO model of skin aging. Male C57BL/6 wild type and apoE-KO mice were grown for 0, 5, 15 or 30. weeks on either a high fat (21.2{\%} fat, 0.2{\%} cholesterol) or regular chow diet (7{\%} fat). ApoE/GrB double knockout (DKO) mice were also generated and assessed after being fed either diet for 30. weeks. Skin was removed from the mid to lower back and examined for age-related changes such as hair loss, skin thinning and collagen remodeling and disorganization. ApoE-KO mice exhibited signs of frailty, hair graying, hair loss, skin thinning, loss of collagen density and increased skin pathologies featuring collagen remodeling and reduced decorin compared to wild type controls. These phenotypes occurred earlier and were more severe when fed a high fat diet. In addition, we also observed increased GrB expression in proximity to areas of decorin degradation and reduced collagen density in the skin of apoE-KO mice. DKO mice exhibited protection against skin thinning, ECM degradation and loss of dermal collagen density. In summary, our results provide novel insights into the effects of a high fat diet and apoE deficiency on skin aging and pathology and suggest a role for GrB in age-related skin thinning and frailty.",
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Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice. / Hiebert, Paul R.; Boivin, Wendy A.; Abraham, Thomas; Pazooki, Sara; Zhao, Hongyan; Granville, David J.

In: Experimental Gerontology, Vol. 46, No. 6, 01.06.2011, p. 489-499.

Research output: Contribution to journalArticle

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