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(Circulation Research. 2001;88:70.)
© 2001 American Heart Association, Inc.

Cellular Biology

Overexpression of 12-Lipoxygenase Causes Cardiac Fibroblast Cell Growth

Yeshao Wen, Jiali Gu, Yaxia Liu, Ping H. Wang, Yanyu Sun, Jerry L. Nadler

From the Division of Endocrinology and Metabolism (Y.W., J.G., J.L.N.), University of Virginia Health Sciences Center (Charlottesville); Department of Diabetes, Endocrinology and Metabolism (Y.L., Y.S.), City of Hope Medical Center, Duarte, Calif; and Department of Medicine and Biological Chemistry (P.H.W.), University of California (Irvine).

Correspondence to Jerry L. Nadler, MD, Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, MR4 Building, Room 5150, Lane Road, Charlottesville, VA 22908. E-mail jln2n{at}virginia.edu

Abstract—Evidence suggests that leukocyte type 12-lipoxygenase (12-LO) plays an important role in cell growth. However, the role of 12-LO in cardiac cell growth has not been tested. We have now stably overexpressed 12-LO cDNA in rat fetal cardiac fibroblasts to evaluate the role of the 12-LO pathway in cardiac cell growth. Overexpression of 12-LO increased cell [³H]leucine incorporation by 2.1±0.1-fold (P<0.01) and cell protein content by 2.2±0.3-fold (P<0.01) over mock-transfected cells. These findings were confirmed in additional clones. Baicalein, a 12-LO enzyme inhibitor, dose-dependently inhibited serum-induced leucine incorporation in cardiac fibroblast cells as well as partially inhibited leucine incorporation in cells overexpressing 12-LO. 12-LO overexpression also caused cell [³H]thymidine incorporation to increase by 3.4±0.3-fold (P<0.01). Cell flow cytometry analysis showed that the size of 12-LO–overexpressing cells was markedly enlarged compared with that of mock-transfected cells. The fibronectin content of the 12-LO–overexpressing cardiac fibroblasts was also significantly increased. We next evaluated the effects of 12-LO RNA overexpression on kinase pathways linked to cellular growth. The overexpression of 12-LO enhanced extracellular signal-regulated kinase activity (4.1±0.5-fold), c-Jun NH₂-terminal kinase activity (2.9±0.5-fold), and p38 mitogen-activated protein kinase activity (2.2±0.3-fold). Pretreatment with SB202190 (100 nmol/L), a specific inhibitor of p38, prevented the increases in protein content of 12-LO–overexpressing cardiac fibroblast cells. These data clearly demonstrate that the overexpression of 12-LO causes cell growth of cardiac fibroblasts, thus supporting the role of 12-LO as a novel growth-promoting pathway in the heart.

Key Words: lipoxygenase • HETE • cell proliferation • cells

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