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.
| 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 |
