Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells.
Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells.
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DOI：
10.14814/phy2.15544
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发表时间：
2023-01
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
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缺口对血管内稳态至关重要。我们研究了caveolin‐1 （Cav‐1）在介导酒精（乙醇/乙醇）对血管细胞中Notch信号必需的γ -分泌酶蛋白水解活性的影响中的机制作用。用EtOH （0-50 mM）、Notch配体δ样配体4 （Dll4）和γ -分泌酶抑制剂DAPT处理人冠状动脉内皮细胞（HCAEC）。EtOH刺激了HCAEC中的Notch信号传导，其证据是Notch受体（N1, N4）和靶基因（hrt2, hrt3） mRNA水平升高，且在25 mM EtOH下达到最强烈的反应。乙醇（25 mM）刺激HCAEC膜中γ -分泌酶的蛋白水解活性，其程度与Dll4相同。乙醇抑制HCAEC中Cav‐1 mRNA和蛋白水平。Cav‐1敲低可刺激HCAEC中的γ -分泌酶活性，而Cav‐1过表达可抑制γ -分泌酶活性。此外，Cav‐1过表达阻断了EtOH对HCAEC中γ‐分泌酶活性的刺激作用。虽然EtOH也能抑制人冠状动脉平滑肌细胞（HCASMC）中Cav‐1的表达，但EtOH抑制HCASMC中γ‐分泌酶的活性与其在HCAEC中的作用相反。在HCASMC中，EtOH对γ -分泌酶的抑制作用可通过Cav‐1敲低来模拟，并可通过Cav‐1过表达来阻止，这表明在这些细胞中，Cav‐1正调控γ -分泌酶的活性。综上所述，EtOH对动脉EC和SMC中γ -分泌酶活性的调节存在差异，分别具有刺激和抑制作用。这些作用都是通过抑制小窝蛋白- 1介导的，而小窝蛋白- 1本身对两种细胞类型中的γ -分泌酶有相反的作用。这一机制可能在一定程度上解释了适度饮酒对动脉硬化的影响。乙醇（EtOH）抑制内皮细胞（EC）和平滑肌细胞（SMC）中caveolin‐1 （Cav‐1）的表达。Caveolin‐1负性调节EC中的γ -分泌酶活性，而正性调节SMC中的γ -分泌酶活性。因此，酒精对EC和SMC中Cav‐1表达的抑制分别导致Notch信号的增加和减少。EC和SMC中Notch信号的差异变化有望协同维持血管稳态并防止动脉硬化。
Notch is important to vessel homeostasis. We investigated the mechanistic role of caveolin‐1 (Cav‐1) in mediating the effects of alcohol (Ethanol/EtOH) on the γ‐secretase proteolytic activity necessary for Notch signaling in vascular cells. Human coronary artery endothelial cells (HCAEC) were treated with EtOH (0–50 mM), Notch ligand delta‐like ligand 4 (Dll4), and the γ‐secretase inhibitor DAPT. EtOH stimulated Notch signaling in HCAEC as evidenced by increased Notch receptor (N1, N4) and target gene (hrt2, hrt3) mRNA levels with the most robust response achieved at 25 mM EtOH. Ethanol (25 mM) stimulated γ‐secretase proteolytic activity, to the same extent as Dll4, in HCAEC membranes. Ethanol inhibited Cav‐1 mRNA and protein levels in HCAEC. Caveolin‐1 negatively regulated γ‐secretase activity in HCAEC as Cav‐1 knockdown stimulated it, while Cav‐1 overexpression inhibited it. Moreover, Cav‐1 overexpression blocked the stimulatory effect of EtOH on γ‐secretase activity in HCAEC. Although EtOH also inhibited Cav‐1 expression in human coronary artery smooth muscle cells (HCASMC), EtOH inhibited γ‐secretase activity in HCASMC in contrast to its effect in HCAEC. The inhibitory effect of EtOH on γ‐secretase in HCASMC was mimicked by Cav‐1 knockdown and prevented by Cav‐1 overexpression, suggesting that in these cells Cav‐1 positively regulates γ‐secretase activity. In conclusion, EtOH differentially regulates γ‐secretase activity in arterial EC and SMC, being stimulatory and inhibitory, respectively. These effects are both mediated by caveolin‐1 inhibition which itself has opposite effects on γ‐secretase in the two cell types. This mechanism may underlie, in part, the effects of moderate drinking on atherosclerosis. Alcohol (EtOH) inhibits caveolin‐1 (Cav‐1) expression in both endothelial cells (EC) and smooth muscle cells (SMC). Caveolin‐1 negatively regulates gamma‐secretase activity in EC, whereas it positively regulates gamma‐secretase activity in SMC. Thus, alcohol‘s inhibition of Cav‐1 expression in EC and SMC results in increased and decreased Notch signaling, respectively. These differential changes in Notch signaling in EC and SMC would be expected to act synergistically to maintain vessel homeostasis and prevent arteriosclerosis.
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影响因子：
4.4
作者：
Briot A;Bouloumié A;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
3.2
作者：
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DOI：
10.1161/01.atv.0000070546.16946.3a
发表时间：
2003-07-01
影响因子：
8.7
作者：
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通讯作者：
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影响因子：
5.5
作者：
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DOI：
10.1161/hypertensionaha.116.08278
发表时间：
2017-01
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
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作者：
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通讯作者：
Rizzo V