Arteriosclerosis is the leading cause of death in western society. An important event in arteriosclerosis involves the transition of vascular smooth muscle cells (VSMC) from a differentiated to a proliferative phenotype. The genetic switches that regulate this transition are not completely understood. Our goal is to identify nodal regulators that control this process. The non-histone high mobility group chromatin protein HMG-I(Y) is an ideal candidate because it is thought to play a key role in cell proliferation. In addition, it acts as an ~architectural"""""""" transcription factor by altering chromatin structure and recruiting multiple transcription factors to form an """"""""enhanceosome."""""""" Thus, it regulates the function of these transcription factors. We hypothesize that this protein is a critical effector of VSMC proliferation after injury. We have shown that the mRNA of HMG-I(Y) is undetectable in normal arteries but is markedly induced in VSMC after vascular injury. In addition, we have shown that overexpression of HMG-I(Y) in cultured VSMC causes increased transcription of the cell cycle gene cyclin A, a marker for cell proliferation. To our knowledge, this is the first example of a growth-related gene that is regulated by HMG-I(Y). We have generated stable clones that overexpress HMG-I(Y) and will assess their phenotype with regard to proliferation, migration and expression of differentiation markers. We plan to identify and characterize the cis-acting elements of the cydin A promoter that confer responsiveness to HMG-I(Y) by reporter gene transfection. In addition, we plan to identify the transcription factors that interact with HMG-I(Y) by interaction cloning with the yeast 2-hybrid system. This proposal aims to improve our fundamental understanding of smooth muscle dedifferentiation and growth during vascular remodeling, which will aid in design of therapies for arteriosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL003745-03
Application #
6030406
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (M1))
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Sakata, Yasuhiko; Kamei, Caramai N; Nakagami, Hironori et al. (2002) Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc Natl Acad Sci U S A 99:16197-202