Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation.
OBJECTIVE
The risk of cardiovascular disease is increased by up to 33 to 50× in chronic inflammatory states and convention doses of statins may not provide the same cardiovascular protection as in noninflamed patients. This study investigated whether the increase in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R)-mediated cholesterol synthesis observed under inflammatory stress was resistant to the action of statins and if so, whether this was because of interference with the sterol regulatory element binding protein cleavage-activating protein pathway.


RESULTS
Inflammatory stress was induced by adding cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) and lipopolysaccharides to vascular smooth muscle cells in vitro and by subcutaneous casein injection in apolipoprotein E/scavenger receptors class A/CD36 triple knockout mice in vivo. Inflammatory stress exacerbated cholesterol ester accumulation and was accompanied in vitro and in vivo by increased HMGCoA-R mRNA and protein expression mediated via activation of the sterol regulatory element binding protein cleavage-activating protein/sterol regulatory element binding protein-2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro. However, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 16 μmol/L inhibited HMGCoA-R activity by 50% in vascular smooth muscle cells, but the same concentration resulted in only 30% of HMGCoA-R activity in vascular smooth muscle cells in the presence of interleukin-1β. Knocking down sterol regulatory element binding protein cleavage-activating protein prevented statin resistance induced by interleukin-1β, and overexpression of sterol regulatory element binding protein cleavage-activating protein induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease aortic lipid accumulation rose from 2 to 10 mg/kg per day in the presence of inflammatory stress.


CONCLUSIONS
Increased cholesterol synthesis mediated by HMGCoA-R under inflammatory stress may be one of the mechanisms for intracellular lipid accumulation and statin resistance.
From the Key Laboratory of Metabolism on Lipid and Glucose, Centre for Lipid Research, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China (Y.C., L.Z., Q.L., A.H., X.Z.R.); Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan (L.C.L.); and John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, United Kingdom (H.K., D.C.W., Z.V., J.F.M., S.H.P., X.Z.R.).
Yaxi
Y
Chen
Halcyon
H
Ku
Lei
L
Zhao
David C
DC
Wheeler
Lung-Chih
LC
Li
Qing
Q
Li
Zac
Z
Varghese
John F
JF
Moorhead
Stephen H
SH
Powis
Ailong
A
Huang
Xiong Z
XZ
Ruan
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D000069059:Atorvastatin; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D025461:Feedback, Physiological; D056945:Hep G2 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D007249:Inflammation / Q000097:blood / Q000201:enzymology*; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics; D013312:Stress, Physiological; D013997:Time Factors; D014162:Transfection
D001057:Apolipoproteins E; D018955:CD36 Antigens; D002791:Cholesterol, Dietary; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011758:Pyrroles; C102196:SREBP cleavage-activating protein; D051117:Scavenger Receptors, Class A; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases
cholesterol; drug resistance; inflammation; statins