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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:541.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Oleate Induces a Myofibroblast-Like Phenotype in Mesangial Cells

Rangnath Mishra; Michael S. Simonson

From the Division of Nephrology and Hypertension, Department of Medicine, Case Western Reserve University and University Hospital Case Medical Center, Cleveland Ohio.

Correspondence to Michael S. Simonson, Department of Medicine, Division of Nephrology, Biomedical Research Building, Rm. 427, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106. E-mail mss5{at}po.cwru.edu

Objective— High circulating free fatty acids, commonly associated with obesity and insulin resistance, impair structure and function of the microvasculature. However, the mechanisms by which fatty acids cause microvascular remodeling are unclear. Using the mesangial cell model of microvascular pericytes, we demonstrate that the monounsaturated free fatty acid oleate induces a myofibroblast phenotype, an important cell fate transition in fibrotic remodeling of the extracellular matrix.

Materials and Results— Oleate induced a time- and dose-dependent increase in secretion of collagen I and fibronectin. Oleate also induced the myofibroblast phenotype markers smooth muscle actin and ED-A fibronectin, and the magnitude of marker protein expression was similar to that for transforming growth factor (TGF)-β. Oleate raised TGF-β secretion 2.2-fold, and processing of latent to bioactive TGF-β was also elevated. Oleate rapidly stimulated extracellular signal-regulated kinase1/2, and a pharmacological MEK inhibitor blocked TGF-β secretion and conversion to the myofibroblast phenotype. A neutralizing TGF-β antibody and a TGF-β receptor kinase inhibitor blocked oleate-induced collagen I, smooth muscle actin, and ED-A fibronectin, suggesting that oleate-stimulated TGF-β was necessary for inducing myofibroblasts.

Conclusions— Collectively, these results demonstrate that oleate can induce a myofibroblast phenotype in mesangial cells, which suggests a mechanism whereby elevated free fatty acids might promote microvascular remodeling in vivo.

Here, we demonstrate that the free fatty acid oleate induces a myofibroblast phenotype in microvascular pericytes. This oleate-induced conversion suggests a mechanism whereby elevated free fatty acids could affect a profibrotic shift in pericyte phenotype and microvascular remodeling.

Key Words: mesangial cells • microvascular • pericytes • free fatty acids • TGF-β; fibrosis