HMG-CoA reductase inhibitors induce apoptosis in pericytes.
Pericytes, which surround endothelial cells in precapillary arterioles, capillaries, and postcapillary venules, are important for the development, maturation, and maintenance of the vascular system. Pericytes are also pluripotent cells that can differentiate into a variety of mesenchymal cells including smooth muscle cells and osteoblasts. Possibly because of their vasculature regulating activities and ability to differentiate in situ, pericytes are implicated in several diseases with vascular complications, including diabetic retinopathy, as well as Reynaud's Syndrome, central nervous system dementias, and vascular calcification among others. Statin drugs, which block the conversion of HMG-CoA to mevalonate in the cholesterol synthesis pathway, are known to have apoptotic and growth inhibitory effects on cells in vitro and complex pleiotropic effects on cells and tissues in vivo. Recently, evidence has emerged that statin drug use in human patients results in a significant 20% reduction in cancer incidence. It is not known whether these results are due to direct statin action on normal tissue, growth inhibitory/pro-apoptotic effects on tumor cells, and/or effects on angiogenesis. Because of the role of pericytes in angiogenesis and the effects of statins on cancer incidence, we tested the direct effects of statins on pericytes. Specifically, we demonstrate that 3 statins, simvastatin, lovastatin, and mevastatin induce dose-dependent apoptosis in the TR-PCT1 pericyte cell line, that simvastatin (empirically shown to be the most potent of the 3 statins) induces similar levels of apoptosis in freshly isolated pericytes, and that simvastatin-induced apoptosis in pericytes is cholesterol, caspase-3, and caspase-7 mediated.
Boucher
Kelly
K
Department Orthopaedic Surgery, Children's Hospital Boston, Boston, MA 02115, USA.
Siegel
Chad S
CS
Sharma
Parul
P
Hauschka
Peter V
PV
Solomon
Keith R
KR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D020286:Pericytes / Q000201:enzymology* / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology; D013997:Time Factors
D002867:Chromones; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009025:Morpholines; C012258:mevastatin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D008148:Lovastatin; D019821:Simvastatin