Overexpression of 12-lipoxygenase and cardiac fibroblast hypertrophy.
Leukocyte-type 12-lipoxygenase (12-LO) catalyzes the conversion of arachidonic acid (C20:4) to 12-hydroperoxyeicosatetraenoic acid, which in turn reduces to 12-hydroxyeicosatetraenoic acid (12-HETE) by glutathione peroxidase. Results of studies in vascular smooth muscle and in adrenal glomerulosa cells have supported the concept that 12-LO is an important mediator of angiotensin II (Ang II) action. Studies also indicate that 12-HETE is a potent growth-promoting factor and facilitates proliferation in Chinese hamster ovary (CHO) fibroblast cells overexpressing the Ang II AT1a receptor (CHO-AT1a cells). However, until recently, the role of 12-LO in cardiac cells had not been explored. Cardiac fibroblasts are a major source of matrix proteins, which can lead directly to extracellular matrix deposition and cardiac fibrosis. To elucidate the role of the 12-LO pathway in fibroblast cell growth, 12-LO cDNA was stably transfected into fetal rat cardiac fibroblasts. The cells overexpressing 12-LO showed an increase in cell protein content and enlargement in cell size with a slowing of cell division rate. Furthermore, the cells overexpressing 12-LO showed increases in fibronectin and collagen deposition compared with mock-transfected cells. These features are most consistent with cellular hypertrophy instead of proliferation. It is proposed that cardiac fibroblast cells overexpressing 12-LO retain the characteristics of fibroblasts, but with additional features of myocytes that have the function of showing cell hypertrophy. These results provide the basis for proposing the hypothesis that enhanced 12-LO expression or activity could play a role in pathogenic cardiac enlargement.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health Science Center, Charlottesville 22908, USA. yw4w@virginia.edu
Yeshao
Y
Wen
Jiali
J
Gu
Xianghong
X
Peng
Guoxiang
G
Zhang
Jerry
J
Nadler
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis*; D006332:Cardiomegaly / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology
D015289:Leukotrienes; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C021201:12-HPETE; D001092:Arachidonate 12-Lipoxygenase