The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis.
The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.
Sasaki
Makoto
M
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Bharwani
Sulaiman
S
Jordan
Paul
P
Joh
Takashi
T
Manas
Kenneth
K
Warren
April
A
Harada
Hirohisa
H
Carter
Patsy
P
Elrod
John W
JW
Wolcott
Michael
M
Grisham
Matthew B
MB
Alexander
J Steven
JS
D000818:Animals; D015815:Cell Adhesion Molecules; D002463:Cell Membrane Permeability / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007136:Immunoglobulins / Q000032:analysis; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis
D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D012333:RNA, Messenger; D016264:Dextran Sulfate; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017035:Pravastatin