HUMAN PRIMARY VASCULAR SMOOTH MUSCLE CELL CULTURE

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose that iron plays a critical role in cardiovascular diseases: vascular smooth muscle cell (VSMC) migration and proliferation. To test this hypothosis we will employ an extraordinary family of iron chelators that we have described and synthesized. This family is exochelins, siderophores secreted by Mycobacterium tuberculosis. They block the iron-dependent production of highly toxic hydroxyl radical (oOH). Exochelins are unique in that they are lipid soluble, a property that we postulate enables them to rapidly enter cells and localize in the lipid portion of the cell membrane where critical iron-mediated processes occur. Desferri-exochelins (D-Exo) also prevent growth of cultured vascular smooth muscle cells. We will employ exochelins to gain insights into the iron-dependent mechanisms leading to vascular smooth muscle growth. Iron is a ubiquitous metal in cells and is present in many enzymes and proteins. One of the molecules necessary for cell proliferation is ribonucleotide reductase (RR), an iron requiring enzyme. RR is indispensable for the reduction of ribonucleotides to deoxyribonulceotides, a critical step in DNA synthesis. we have done micro array analysis on D-Exo treated cells and found that one molecule that is consistently up-regulated is peroxisome proliferator-activated receptor-gamma. PPAR ligands have been shown to inhibit growth of vascular and cancer cells by interfering with the expression and function of multiple cell cycle regulators in these cells. We propose to test the hypothesis that D-Exo inhibits human vascular smooth muscle cell proliferation by inhibiting the cell cycle exit from G1 into S phase by attenuating Rb phosphorylation through PPAR.