Nitric oxide decreases activity and levels of the 11S proteasome activator PA28 in the vasculature

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• 作者：Nick D. Tsihlis^a ; ¹ ; Muneera R. Kapadia^a ; ¹ ; Ashley K. Vavra^a ; Qun Jiang^a ; Bo Fu^a ; Janet Martinez^a ; Melina R. Kibbe^a ; ^b ; ^{mkibbe@nmh.org}
• 关键词：Arterial injury ; Neointimal hyperplasia ; Nitric oxide ; Proteasome activator ; PA28 ; Vascular smooth muscle cells
• 刊名：Nitric Oxide
• 出版年：2012
• 出版时间：30 June, 2012
• 年：2012
• 卷：27
• 期：1
• 页码：50-58
• 全文大小：1338 K

文摘

The 11S proteasome activator (PA28) binds to the 20S proteasome and increases its ability to degrade small peptides. Expression of PA28 subunits (¦Á, ¦Â, ¦Ã) is induced by interferon-¦Ã stimulation. Inflammation plays a role in the development of neointimal hyperplasia, and we have previously shown that nitric oxide (NO) reduces neointimal hyperplasia in animal models and 26S proteasome activity in rat aortic smooth muscle cells (RASMC). Here, we show that PA28 increased 26S proteasome activity in RASMC, as measured by a fluorogenic assay, and the NO donor S-nitroso N-acetylpenicillamine significantly inhibits this activation. This effect was abrogated by the reducing agents dithiothreitol and HgCl₂, suggesting that NO affects the activity of PA28 through S-nitrosylation. NO did not appear to affect PA28 levels or intracellular localization in RASMC in vitro. Three days following rat carotid artery balloon injury, levels of PA28¦Á, ¦Â and ¦Ã subunits were decreased compared to uninjured control arteries (n = 3/group) in vivo. The NO donor proline NONOate further decreased PA28¦Á, ¦Â and ¦Ã levels by 1.9-, 2.3- and 3.4-fold, respectively, compared to uninjured control arteries. Fourteen days following arterial injury, levels of PA28¦Á, ¦Â and ¦Ã subunits were increased throughout the arterial wall compared to uninjured control arteries, but were greatest for the ¦Á and ¦Â subunits. NO continued to decrease the levels of all three PA28 subunits throughout the arterial wall at this time point. Since the PA28 subunits are involved in the breakdown of peptides during inflammation, PA28 inhibition may be one mechanism by which NO inhibits neointimal hyperplasia.