Abstract/Details

The roles of calpain and protein kinase C in type 1 diabetic vascular dysfunction


2010 2010

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Abstract (summary)

Endothelial dysfunction is an early change associated with cardiovascular disease in diabetes. The calcium-dependent protease calpain is activated in the endothelium by acute hyperglycemia and type 2 diabetes. The endothelial dysfunction associated with diabetic calpain activity is astonishingly similar to that caused by diabetic PKC activity. Biochemical studies indicate bidirectional crosstalk between calpain and PKC in vitro. Therefore, we hypothesized that type 1 diabetes activates vascular calpain in the signaling cascade of vascular PKC to induce endothelial dysfunction in type 1 diabetes.

Measurements of the proteolysis of a fluorogenic calpain substrate indicated increased calpain activity in the mesenteric microvasculature of type 1 diabetic rats. Using intravital microscopy, the calpain signal was localized to the endothelium of mesenteric post-capillary venules in vivo. In vitro studies demonstrated that endothelial calpain is activated acutely by hyperglycemia, which is the hallmark of type 1 diabetes.

Radioactive measurements indicated that PKC is activated independently of calpain in the type 1 diabetic vasculature. Conversely, type 1 diabetes activates endothelial calpain downstream of PKC, as demonstrated by intravital microscopy of mesenteric post-capillary venules. Local hyperglycemia of the mesenteric microvasculature also increases endothelial calpain in a PKC-dependent manner, thus identifying hyperglycemia as a key activator of PKC-calpain signaling in type 1 diabetes. In vitro experiments implicated the PKC β isoform in the activation of endothelial calpain, and western blot analysis revealed that type 1 diabetes preferentially activates the vascular ì-calpain isoform.

Indexing (details)


Subject
Physiology
Classification
0719: Physiology
Identifier / keyword
Biological sciences, Calpain, Diabetes, Protein kinase C, Vascular dysfunction
Title
The roles of calpain and protein kinase C in type 1 diabetic vascular dysfunction
Author
Smolock, Amanda R.
Number of pages
148
Publication year
2010
Degree date
2010
School code
0272
Source
DAI-B 71/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124067421
Advisor
Scalia, Rosario; Butler, Thomas
Committee member
Eckhart, Andrea; Eto, Masumi; Flynn, John
University/institution
Thomas Jefferson University
Department
Molecular Physiology and Biophysics
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3409361
ProQuest document ID
612701638
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/612701638
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