Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells
Abstract 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) we...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-01-01
|
| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15544 |
| _version_ | 1797397093228216320 |
|---|---|
| author | Naresh K. Rajendran Weimin Liu Paul A. Cahill Eileen M. Redmond |
| author_facet | Naresh K. Rajendran Weimin Liu Paul A. Cahill Eileen M. Redmond |
| author_sort | Naresh K. Rajendran |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T01:06:00Z |
| format | Article |
| id | doaj.art-b94e02ce43f3414298044e136be6ce27 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:06:00Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-b94e02ce43f3414298044e136be6ce272023-12-11T10:10:46ZengWileyPhysiological Reports2051-817X2023-01-01111n/an/a10.14814/phy2.15544Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cellsNaresh K. Rajendran0Weimin Liu1Paul A. Cahill2Eileen M. Redmond3Department of Surgery University of Rochester Medical Center Rochester New York USADepartment of Surgery University of Rochester Medical Center Rochester New York USAVascular Biology and Therapeutics Laboratory, School of Biotechnology Dublin City University Dublin IrelandDepartment of Surgery University of Rochester Medical Center Rochester New York USAAbstract 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.https://doi.org/10.14814/phy2.15544alcoholatherosclerosiscardiovascularNotch |
| spellingShingle | Naresh K. Rajendran Weimin Liu Paul A. Cahill Eileen M. Redmond Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells Physiological Reports alcohol atherosclerosis cardiovascular Notch |
| title | Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells |
| title_full | Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells |
| title_fullStr | Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells |
| title_full_unstemmed | Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells |
| title_short | Caveolin‐1 inhibition mediates the opposing effects of alcohol on γ‐secretase activity in arterial endothelial and smooth muscle cells |
| title_sort | caveolin 1 inhibition mediates the opposing effects of alcohol on γ secretase activity in arterial endothelial and smooth muscle cells |
| topic | alcohol atherosclerosis cardiovascular Notch |
| url | https://doi.org/10.14814/phy2.15544 |
| work_keys_str_mv | AT nareshkrajendran caveolin1inhibitionmediatestheopposingeffectsofalcoholongsecretaseactivityinarterialendothelialandsmoothmusclecells AT weiminliu caveolin1inhibitionmediatestheopposingeffectsofalcoholongsecretaseactivityinarterialendothelialandsmoothmusclecells AT paulacahill caveolin1inhibitionmediatestheopposingeffectsofalcoholongsecretaseactivityinarterialendothelialandsmoothmusclecells AT eileenmredmond caveolin1inhibitionmediatestheopposingeffectsofalcoholongsecretaseactivityinarterialendothelialandsmoothmusclecells |