An Unexpected Enzyme in Vascular Smooth Muscle Cells: Angiotensin II Upregulates Cholesterol-25-Hydroxylase Gene Expression

An Unexpected Enzyme in Vascular Smooth Muscle Cells: Angiotensin II Upregulates Cholesterol-25-Hydroxylase Gene Expression

Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H), also have detrimental effects on vascular h...

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Bibliographic Details
Main Authors: Kinga Bernadett Kovács, Laura Szalai, Pál Szabó, Janka Borbála Gém, Szilvia Barsi, Bence Szalai, Bernadett Perey-Simon, Gábor Turu, András Dávid Tóth, Péter Várnai, László Hunyady, András Balla
Format: Article
Language:English
Published: MDPI AG 2023-02-01
Series:International Journal of Molecular Sciences
Subjects:
angiotensin II
atherosclerosis
cholesterol-25-hydroxylase
25-hydroxycholesterol
vascular smooth muscle cell
Online Access:https://www.mdpi.com/1422-0067/24/4/3968
Description
Summary:Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H), also have detrimental effects on vascular health by affecting vascular smooth muscle cells (VSMCs). We investigated AngII-induced gene expression changes in VSMCs to explore whether AngII stimulus and 25-HC production have a connection in the vasculature. RNA-sequencing revealed that <i>Ch25h</i> is significantly upregulated in response to AngII stimulus. The <i>Ch25h</i> mRNA levels were elevated robustly (~50-fold) 1 h after AngII (100 nM) stimulation compared to baseline levels. Using inhibitors, we specified that the AngII-induced <i>Ch25h</i> upregulation is type 1 angiotensin II receptor- and G<sub>q/11</sub> activity-dependent. Furthermore, p38 MAPK has a crucial role in the upregulation of <i>Ch25h</i>. We performed LC-MS/MS to identify 25-HC in the supernatant of AngII-stimulated VSMCs. In the supernatants, 25-HC concentration peaked 4 h after AngII stimulation. Our findings provide insight into the pathways mediating AngII-induced <i>Ch25h</i> upregulation. Our study elucidates a connection between AngII stimulus and 25-HC production in primary rat VSMCs. These results potentially lead to the identification and understanding of new mechanisms in the pathogenesis of vascular impairments.
ISSN:1661-6596
1422-0067

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