TY - JOUR
T1 - Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells
AU - Stark, William W.
AU - Blaskovich, Michelle A.
AU - Johnson, Bruce A.
AU - Qian, Yimin
AU - Vasudevan, Anil
AU - Pitt, Bruce
AU - Hamilton, Andrew D.
AU - Sebti, Saïd M.
AU - Davies, Paul
PY - 1998/7
Y1 - 1998/7
N2 - The activity of small GTP-binding proteins is regulated by a critical step in posttranslational processing, namely, the addition of isoprenoid lipids farnesyl and geranylgeranyl, mediated by the enzymes farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I), respectively. We have developed compounds that inhibit these enzymes specifically and in this study sought to determine their effects on smooth muscle cells (SMC) from the pulmonary microvasculature. We found that the GGTase I inhibitor GGTI-298 suppressed protein geranylgeranylation and blocked serum-dependent growth as measured by thymidine uptake and cell counts. In the absence of serum, however, GGTI-298 induced apoptosis in these cells as measured by both DNA staining and flow cytometry. The FTase inhibitor FTI-277 selectively inhibited protein farnesylation but had a minor effect on growth and no effect on apoptosis. To further investigate the role of geranylgeranylated proteins in apoptosis, we added the cholesterol synthesis inhibitor lovastatin, which inhibits the biosynthesis of farnesyl and geranylgeranyl pyrophosphates. This also induced apoptosis, but when geranylgeraniol was added to replenish cellular pools of geranylgeranyl pyrophosphate, apoptosis was reduced to baseline. In contrast, farnesol achieved only partial rescue of the cells. These results imply that geranylgeranylated proteins are required for growth and protect SMC against apoptosis. GGTase I inhibitors may be useful in preventing hyperplastic remodeling and may have the potential to induce the apoptotic regression of established vascular lesions.
AB - The activity of small GTP-binding proteins is regulated by a critical step in posttranslational processing, namely, the addition of isoprenoid lipids farnesyl and geranylgeranyl, mediated by the enzymes farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I), respectively. We have developed compounds that inhibit these enzymes specifically and in this study sought to determine their effects on smooth muscle cells (SMC) from the pulmonary microvasculature. We found that the GGTase I inhibitor GGTI-298 suppressed protein geranylgeranylation and blocked serum-dependent growth as measured by thymidine uptake and cell counts. In the absence of serum, however, GGTI-298 induced apoptosis in these cells as measured by both DNA staining and flow cytometry. The FTase inhibitor FTI-277 selectively inhibited protein farnesylation but had a minor effect on growth and no effect on apoptosis. To further investigate the role of geranylgeranylated proteins in apoptosis, we added the cholesterol synthesis inhibitor lovastatin, which inhibits the biosynthesis of farnesyl and geranylgeranyl pyrophosphates. This also induced apoptosis, but when geranylgeraniol was added to replenish cellular pools of geranylgeranyl pyrophosphate, apoptosis was reduced to baseline. In contrast, farnesol achieved only partial rescue of the cells. These results imply that geranylgeranylated proteins are required for growth and protect SMC against apoptosis. GGTase I inhibitors may be useful in preventing hyperplastic remodeling and may have the potential to induce the apoptotic regression of established vascular lesions.
KW - Lovastatin
KW - Prenyltransferase inhibitors
KW - Pulmonary vasculature
UR - http://www.scopus.com/inward/record.url?scp=0031814992&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031814992&partnerID=8YFLogxK
U2 - 10.1152/ajplung.1998.275.1.l55
DO - 10.1152/ajplung.1998.275.1.l55
M3 - Article
C2 - 9688935
AN - SCOPUS:0031814992
SN - 1040-0605
VL - 275
SP - L55-L63
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 1 19-1
ER -