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VASCULAR AND HYPERTENSION

Blockade of Endothelin-1 Release Contributes to the Anti-Angiogenic Effect by Pro-Opiomelanocortin Overexpression in Endothelial Cells

Hing-Chung Lam^*,,||,1,2, Shiao-Mei Kuo^*,, Ming-Ju Chuang, Hsiu-Man Keng, Pey-Ru Lin^*, Guei-Sheung Liu^*,, Ching-Mei Hsu, Shen-Long Howng and Ming-Hong Tai^*,,,2

^* Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; and ^|| National Yang-Ming University School of Medicine, Taipei, Taiwan

To whom requests for reprints should be addressed at ¹ Division of Medical Research, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386, Ta-Chung 1st Rd., Kaohsiung, Taiwan 813, Republic of China. E-mail: hclam{at}isca.vghks.gov.tw or mhtai{at}isca.vghks.gov.tw

Abstract

Pro-opiomelanocortin (POMC) is the precursor of several neuropeptides, such as corticotropin (ACTH), -melanocyte–stimulating hormone (MSH), and the endogenous opioid, ß-endorphin (EP). ACTH-dependent Cushing’s syndrome is characterized by ACTH overproduction and is associated with an increased risk of cardiovascular disease. Endothelial dysfunction has been recognized as an early marker of cardiovascular disease. However, the mechanism underlying endothelial dysfunction by ACTH overexpression in Cushing’s patients remains elusive. Endothelial cells, the primary cells producing endothelin (ET)-1, are both the source and target of POMC-derived peptides. In the present study, we generated adenovirus vectors (Ad) encoding POMC (Ad-POMC) and green fluorescent protein (GFP; Ad-GFP) to investigate whether POMC gene transfer altered the ET-1 homeostasis and angiogenic functions in human EA.hy926 endothelial cells. Via adenovirus gene delivery, the POMC-transduced EA.hy926 cells released significantly elevated ACTH and ß-EP levels (P < 0.001). In addition, POMC gene delivery significantly decreased the ET-1 release (P < 0.001) without affecting the ET-1 messenger RNA (mRNA) level. Despite no effect on the secretion of matrix metalloproteinases (MMPs) and cell proliferation, POMC gene delivery significantly inhibited the migration (P < 0.01) and tube-forming capability (P < 0.01) of endothelial cells. Moreover, the POMC-induced inhibition of tube formation could be partially reversed by adding exogenous ET-1 (P < 0.05). In summary, the attenuated ET-1 release and angiogenic processes by POMC overexpression may contribute to endothelial dysfunction, thereby providing a link between Cushing’s syndrome and cardiovascular diseases.

Key Words: Cushing’s syndrome • POMC • endothelin-1 • endothelial cells • gene delivery