ノックスアクティベーター1: 動脈硬化性動脈における血管活性酸素種を調節する潜在的な標的
Xi-Lin Niu1, Nageswara R Madamanchi, Aleksandr E Vendrov
1McAllister Heart Institute, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-7005, USA.
Circulation
|January 20, 2010
まとめ
ノックスアクティベーター1 (NoxA1) は,血管の滑らかな筋肉細胞NADPH酸化酵素の重要な調節体として特定されています. NoxA1のダウンレギュレーションは,反応性酸素種と増殖を減少させ,血管疾患の潜在的な治療標的を提供します.
科学分野:
- 血管生物学 血管生物学
- 分子医学は分子医学である.
- バイオケミストリー バイオケミストリー
背景:
- 血管の滑らかな筋肉細胞 (VSMC) のNADPH酸化酵素の特定のサブユニットは,ほとんど不明のままです.
- これらのコンポーネントを理解することは,血管疾患に対する標的治療の開発に不可欠です.
研究 の 目的:
- VSMCのNADPH酸化酵素機能におけるp67phoxホモログであるノックスアクティベーター1 (NoxA1) の役割を調査する.
- 動脈硬化症の発達におけるNoxA1の関与を評価する.
主な方法:
- RT-PCRとシーケンシングを用いたマウスのVSMCでNoxA1の存在が確認されました.
- NoxA1/p47phoxの相互作用を研究するために,免疫プレシピテーションとウエスタン分析を使用しました.
- VSMCおよびマウスモデルにおけるNoxA1過剰発現およびshRNAのダウンレギュレーションのためのアデノウイルスベクトルを採用した.
- 分析された反応性酸素種 (ROS) 生成,VSMC増殖,およびリドックス感受性キナーゼの活性化.
- 動脈硬化症 (ApoE-/-) とヒト動脈硬化性病変のマウスモデルにおけるNoxA1発現を調べた.
主要な成果:
- NoxA1過剰発現は,p47phoxとNox1.1に依存する野生型のVSMCで,トロンビン誘発のROS生成を強化した.
- NoxA1のダウンレギュレーションにより,ROSの生成,VSMCの増殖,およびJAK2,Akt,およびp38 MAPKの活性化が低下しました.
- 損傷した頸動脈におけるNoxA1過剰発現は,スーパーオキシドの産生を増加させ,ネオインティマルの高血症を引き起こします.
- NoxA1の発現は,ApoE-/-マウスの動脈硬化性大動脈で上昇し,ヒトの動脈硬化性病変に存在していました.
結論:
- NoxA1は,VSMCにおけるp67phoxホモログとして機能し,レドックスシグナル伝達とVSMCのフェノタイプを調節する.
- NoxA1発現を調節することは,血管疾患に対する有望な治療戦略です.
関連する概念動画
Nitric Oxide Signaling Pathway
Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
Antihypertensive Drugs: Vasodilators
Vasodilators, primarily affecting the smooth muscles within arterial and venous walls, are commonly used for hypertension treatment. Medications such as minoxidil and hydralazine primarily target arteries and arterioles, while sodium nitroprusside acts on arterioles and venules. Minoxidil, functioning as a prodrug, is metabolized by hepatic sulfotransferase into its active form, minoxidil sulfate, after oral administration. This metabolite binds to the sulfonylurea receptor (SUR) component of...
Autoregulation of Blood Flow
Autoregulation mechanisms are characterized by their inherent capacity for self-regulation without necessitating specific nervous stimulation or endocrine control. These mechanisms facilitate the adjustment of blood flow and, therefore, perfusion specific to each tissue region. This self-regulation encompasses chemical signals and myogenic controls.
Chemical Signaling in Autoregulation
Chemical signaling operates at the precapillary sphincter level, inciting either contraction or relaxation.
Chemical Signaling in Autoregulation
Chemical signaling operates at the precapillary sphincter level, inciting either contraction or relaxation.
Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Radical Autoxidation
The oxidation of an organic compound in the presence of air or oxygen is called autoxidation. For example, cumene reacts with oxygen to form hydroperoxide. Autoxidation involves initiation, propagation, and termination steps. Many organic compounds are susceptible to autoxidation—especially ethers in the presence of oxygen, which form hydroperoxides. Even though this reaction is slow, old ether bottles contain small amounts of peroxide, which leads to laboratory explosions during ether...
Antihypertensive Drugs: Action of Calcium Channel Blockers
Calcium ions are essential to contract smooth muscle cells in blood vessels. They enter these cells through voltage-dependent calcium channels, specifically L-type calcium channels in the cell membrane. These L-type calcium channels are integral to the excitation-contraction coupling process in smooth muscle. When a stimulus is received by smooth muscle cells, their membrane depolarizes. This alteration in membrane potential instigates the opening of L-type calcium channels. As a result,...


