HMG-CoA reductase inhibition reduces the proinflammatory activation of human vascular smooth muscle cells by the terminal complement factor C5b-9.
The terminal complement complex C5b-9 is known to participate in inflammatory processes including atherosclerosis. Inflammation appears to be a direct consequence of C5b-9-mediated cell stimulation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may exert anti-inflammatory effects on vascular cells independent of lowering plasma cholesterol. Thus, we studied activation of vascular smooth muscle cells (VSMCs) by C5b-9 focusing on whether inhibition of the HMG-CoA reductase can reduce the proinflammatory effects of C5b-9.C5b-9 in sublytic concentrations increased the proliferation of human VSMCs and induced a time-dependent activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Proliferation and ERK1/2 activation could be inhibited by the specific ERK inhibitor PD98059. HMG-CoA inhibition with cerivastatin-reduced VSMC proliferation and C5b-9-induced ERK1/2 activation. Cerivastatin also reduced the C5b-9-induced synthesis of the proinflammatory interleukin-6 (IL-6). Furthermore, C5b-9 induced activation of the transcription factors activator protein- 1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which could be inhibited by pretreatment of VSMCs with cerivastatin. L-mevalonate and geranylgeranylpyrophosphate reversed the inhibitory effects of cerivastatin. The present study in VSMCs shows that cerivastatin inhibits IL-6 synthesis and cell proliferation induced by the terminal complement complex C5b-9. This may be an important mechanism contributing to the beneficial effects of HMG-CoA reductase inhibitors beyond lowering of plasma cholesterol.
Viedt
Christiane
C
Department of Internal Medicine III, University of Heidelberg, Bergheimer Strasse 58, 69115 Heidelberg, Germany. christiane_viedt@med.uni-heidelberg.de
Shen
Weili
W
Fei
Jianwei
J
Kamimura
Motohiro
M
Hänsch
Gertrud M
GM
Katus
Hugo A
HA
Kreuzer
Jörg
J
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008148:Lovastatin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D015938:Complement Membrane Attack Complex; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016328:NF-kappa B; D011725:Pyridines; D018808:Transcription Factor AP-1; D008148:Lovastatin; C086276:cerivastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases