酸化窒素は,酸化窒素合成酵素のイソフォームを空間的に閉じ込めて心臓を調節する

Lili A Barouch¹, Robert W Harrison, Michel W Skaf

¹Department of Medicine (Cardiology Division), The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.

Nature

|March 22, 2002

まとめ

酸化窒素合成酵素 (NOS1とNOS3) は,心臓の機能において異なる役割を果たしています. これらの酵素の空間的局所化は心臓の収縮性と構造に影響し,NOS1とNOS3は独立した効果を媒介する.

科学分野:

心血管生理学心血管の生理学
分子心臓病学分子心臓病学
セルラー・シグナリング

背景:

酸化窒素 (NO) 合成酵素のサブセルラー局所化は,NOシグナル伝達に極めて重要です.
NOが心筋収縮に及ぼす影響は変動し,L型Ca2+経路とSR Ca2+放出に影響する.
特定のNO合成酵素イソフォーム (NOS1およびNOS3) は,心臓における明確な細胞下標的を持っています.

研究の目的:

心臓の機能を調節する NO 合成酵素の異形態の空間的閉じ込めの役割を調査する.
NOS1とNOS3が心筋の収縮性,構造,ベータアドレネルジック刺激に対する反応に及ぼす独立した効果と併用された効果を決定する.
NOS1とNOS3がCa2+の取り扱いと心臓の改造に影響を与えるメカニズムを解明する.

主な方法:

NOS1欠乏,NOS3欠乏,NOS1/3ダブルノックアウトマウスモデルを使用しました.
評価された心筋収縮性とイノトロプ的応答.
サルコプラズマ網膜 (SR) のCa2+放出とL型Ca2+チャネル機能を調べました.
ノックアウトマウスの心臓構造,高縮,血圧の評価.

主要な成果:

洞窟のNOS3区分化は,L型Ca2+チャネルを調節することによってβ-アドレナジック誘発の収縮性を抑制する.
SRをターゲットとするNOS1は,ライオノジン受容体 (RyR) 介介介 Ca2+放出によって収縮性を促進する.
NOS1欠乏は収縮性を抑制し,NOS3欠乏は収縮性を強化し,SR Ca2+の放出に相関的な変化があった.
NOS1-/-とNOS3-/-の両方のマウスは,年齢関連の高血圧症を示し,NOS3-/-のマウスだけが高血圧であった.
ダブル・ノックアウトマウスは,抑制されたベータアドレナジック反応と添加性心室リモデリングを示した.

結論:

NOS1とNOS3の空間的局所化は,心臓の収縮性におけるそれらの対極的な役割を決定する.
NOS1とNOS3は,心臓の構造と機能に独立した,時には敵対的な影響を及ぼします.
特定のNO合成イソフォームをターゲットにすることは,心臓血管疾患の潜在的な治療戦略を提供します.

さらに関連する動画

08:58

En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries

Published on: February 25, 2016

08:32

Application of Genetically Encoded Fluorescent Nitric Oxide (NO•) Probes, the geNOps, for Real-time Imaging of NO• Signals in Single Cells

Published on: March 16, 2017

関連する概念動画

01:21

Paracrine Signaling

Paracrine signaling allows cells to communicate with their immediate neighbors via secretion of signaling molecules. Such a signal can only trigger a response in nearby target cells because the signal molecules degrade quickly or are inactivated if not taken up. Prominent examples of paracrine signaling include nitric oxide signaling in blood vessels, synaptic signaling of neurons, the blood clotting system, tissue repair/wound healing, and local allergic skin reactions. Nitric oxide as a...

01:28

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...

01:23

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...

01:29

Pathophysiology of Cardiac Performance

Typical heart performance is influenced by heart rate, rhythm, myocardial contraction, and metabolism or blood flow. The cardiac muscle exhibits distinct electrophysiological features, including pacemaker activity and calcium channel control, which play a vital role in the heart's response to various drugs. The autonomic nervous system, comprising the sympathetic and parasympathetic branches, regulates heart rate. Sympathetic activation increases heart rate, while parasympathetic activation...

01:16

Antianginal Drugs: Nitrates and β-Blockers

In cardiovascular health, antianginal drugs combat angina pectoris — a condition marked by chest pain owing to diminished blood flow to the heart.
Organic nitrates, such as nitroglycerin, play a pivotal role. Once metabolized, they liberate nitric oxide, a molecular marvel. Nitric oxide triggers guanylyl cyclase and augments cGMP production. This biochemical cascade orchestrates the relaxation of vascular smooth muscles, ushering in vasodilation and enhancing coronary blood flow. Administered...

01:17

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.

関連する実験動画