Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy.
3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Several large landmark clinical studies have shown a marked reduction of cardiovascular mortality and morbidity in patients treated with statins. Because of the strong association between serum cholesterol levels and coronary artery disease, investigators initially assumed that the predominant beneficial effects of statins result from their lipid-lowering properties. However, more recent observations have suggested that the clinical benefits of statins may be in part independent of their cholesterol-lowering effects. The pleiotropic or cholesterol-independent effects of statins might result from preventing the production of isoprenoids. Isoprenoids serve as important lipid attachments for the post-translational modification of a variety of proteins such as small GTP binding proteins implicated in intracellular signaling. The list of different pleiotropic effects of statins is still growing and, among others, includes the modulatory effects of statins on endothelial function, oxidative stress, coagulation, plaque stability, and inflammation. The pleiotropic effects of statins represent an area of great interest in prevention and therapy of cardiovascular and other chronic diseases. An area of particular interest is the potential beneficial effects of statins in diabetes and its micro/macrovascular complications. This review summarizes our current understanding of the pleiotropic effects of statins in diabetes and the modulatory effects of statins in various pathobiological pathways involved in diabetes and its complications.
Danesh
Farhad R
FR
Division of Nephrology/Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA . f-rahimi@northwestern.edu
Kanwar
Yashpal S
YS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D007333:Insulin Resistance; D008798:Mevalonic Acid / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D012206:Rhabdomyolysis / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000037:antagonists & inhibitors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020558:GTP Phosphohydrolases; D008798:Mevalonic Acid