title: Opposing actions of rosiglitazone and resveratrol on mineralization in human vascular smooth muscle cells.
abstract: Arteriosclerotic vascular disease is a major cardiac health problem in westernized countries and the primary cause of mortality in diabetic patients. Recent data have raised serious safety concerns with the antidiabetic rosiglitazone, a thiazolidinedione with peroxisome proliferator-activated receptor γ (PPAR-γ) agonistic activity, in regard to cardiovascular risks. A common feature of atherosclerosis is vascular mineralization. The latter is formed by vascular smooth muscle cells (VSMC) through complex processes that are similar to mineralization in bone. The aim of the current study was to investigate the effect of rosiglitazone on mineralization in cultured human VSMCs. We found that rosiglitazone stimulated mineralization by, at least in part, induction of caspase-dependent apoptosis. Furthermore, rosiglitazone-induced oxidative stress was correlated with stimulated osteoblast-like differentiation of VSMCs. Treatment of rosiglitazone-supplemented VSMC cultures with the caloric restriction mimetic and antioxidant resveratrol diminished rosiglitazone-induced oxidative stress, osteoblast-like differentiation and mineralization. In conclusion, this study reveals novel insights into the relationship of rosiglitazone and cardiovascular events by providing a model that links rosiglitazone-induced osteoblast-like differentiation, oxidative stress and apoptosis with mineralization in VSMCs. In addition, we position resveratrol in this model acting to reduce rosiglitazone-induced oxidative stress, osteoblast-like VSMC differentiation and mineralization.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bruedigam
authors.forename: Marco
authors.initials: M
authors.lastname: Eijken
authors.forename: Marijke
authors.initials: M
authors.lastname: Koedam
authors.forename: Hideki
authors.initials: H
authors.lastname: Chiba
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000077185:Resveratrol; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D007004:Hypoglycemic Agents; D013267:Stilbenes; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D020169:Caspases; D000077185:Resveratrol