Role of the Lipoxygenase Pathway in Angiotensin II-induced Vascular Smooth Muscle Cell Hypertrophy

The 12-lipoxygenase pathway is a key mediator of angiotensin II (Ang II)-induced effects in the adrenal cortex. We also recently demonstrated that Ang II increases 12- and 15-lipoxygenase product levels in vascular smooth muscle cells. However, the relation between lipoxygenase activation and Ang II-induced vascular smooth muscle cell hypertrophy is not known. We studied the effects of Ang II and 12-lipoxygenase products on both total cell protein content and the levels of the matrix protein fibronectin in quiescent porcine aortic smooth muscle cells. Ang II-induced increases in cellular protein content were attenuated by the specific 12-lipoxygenase inhibitor baicalein; in contrast, the cyclooxygenase inhibitor ibuprofen had no effect. Direct addition of the 12-lipoxygenase product 12-S-hydroxyeicosatetraenoic acid increased total cell protein content. We have recently shown that porcine vascular smooth muscle cell growth is potentiated in high glucose (25 mmol/L) culture conditions. We observed that both Ang II and 12-S-hydroxyeicosatetraenoic acid induced a greater increase in protein content in cells cultured for two passages in high glucose. Furthermore, Ang II and 12-S-hydroxyeicosatetraenoic acid also markedly increased fibronectin levels in cells cultured in high glucose. These results suggest that 12-lipoxygenase activation plays a key role in Ang II-induced vascular smooth muscle cell hypertrophy. Furthermore, both Ang II and lipoxygenase effects are enhanced in cells cultured under hyperglycemic conditions.