Macro- and microangiopathies are one of the major causes of death in the diabetic population of Western countries (1). Although accumulated evidence suggests that diabetes represents mainly an additional risk factor and merely accelerates processes occurring at a slower rate in the general population, because of a marked predilection for the development of atherosclerosis in the peripheral arteries of diabetics, it has been proposed that diabetes-associated atherosclerosis is a distinctive disease. One of the common and early features in the development of atherosclerotic lesions is the migration of smooth muscle cells from the tunica media and their proliferation in the intima (1-3). Although this process is not sufficient, it is required before fibrocellular lesions appear. As long as the smooth muscle cells are contained within the tunica media, they remain fully differentiated, do not replicate and exhibit limited secretory activity. However, if they are allowed to migrate from the tunica media, they rapidly lose their contractile function and become active synthetic cells which invade the tunica intima where they secrete extracellular matrix components, contributing significantly to the formation of atherosclerotic lesions. The purpose of this proposal is to investigate whether diabetes causes significant alterations in the genetic expression of smooth muscle cells and whether these alterations become resistant to insulin therapy after prolonged diabetes. A survey of gene products whose expression may be altered in the diabetic animal can be readily accomplished by comparing in vitro translation products coded by RNA prepared from normal and diabetic animals. Preliminary experiments performed on control and 4-week diabetic rabbits indicate that the levels of a limited number of aortic mRNAs are altered when translation products coded by RNAs isolated from control and diabetic animals are compared. These preliminary results will be confirmed. mRNA which are modulated by diabetes will be cloned and the identification of the proteins for which they code will be initiated. In addition, the expression of selected mRNA coding for the isoforms of actin, myosin heavy chain and for vimentin and fibronectin will be investigated. These proteins are known to play a role in the attachment of cells to the surrounding matrix or in their migration. Changes in mRNAs occurring early in diabetes and which may become increasingly resistant to insulin therapy with the duration of diabetes may be of particular importance in the development of macroangiopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034523-03
Application #
3347495
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1985-09-01
Project End
1989-11-30
Budget Start
1987-09-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093