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Volume 26
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10.3390/ijms26031003
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose

by
Cristina Barale
1,
Giulia Tempesta
1,
Elena Melchionda
1,
Alessandro Morotti
1,
Chiara Frascaroli
2,
Alice Costanza Danzero
1,
Saveria Femminò
1,
Claudia Penna
1 and
Isabella Russo
1,*
1
Department of Clinical and Biological Sciences, Turin University, 10043 Orbassano, Italy
2
San Luigi Gonzaga Hospital, 10043 Orbassano, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(3), 1003; https://doi.org/10.3390/ijms26031003
Submission received: 20 August 2024 / Revised: 6 December 2024 / Accepted: 4 January 2025 / Published: 24 January 2025
(This article belongs to the Special Issue New Advances in Platelet Biology and Functions: 2nd Edition)
Versions Notes

Abstract

Beyond the regulation of cholesterol metabolism, a number of extrahepatic functions of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. The main purpose of this study was to verify whether PCSK9 expression in vascular smooth muscle cells (VSMC) is influenced by insulin resistance and high glucose (HG). In cultured rat aortic VSMC from lean insulin-sensitive Zucker rats (LZRs) and obese insulin-resistant Zucker rats (OZRs), a classical animal model of insulin resistance, we evaluated PCSK9 expression with or without the monoclonal antibodies against PCSK9 Alirocumab and Evolocumab or the synthetic PCSK9-binding peptide PEP 2-8. Effects and molecular mechanisms underlying altered PCSK9 expression were evaluated by proliferation and migration assay, reactive oxygen species (ROS) production, and involvement of PKC, NADPH-oxidase, MAPK/ERK-1/2 pathway activation. As a result, we found that, in comparison with LZR, VSMC from OZR showed basal PCSK9 overexpression mitigated by Alirocumab, Evolocumab, PEP 2-8, and the inhibitors of PKC, NADPH-oxidase, and MAPK. The finding of PCSK9 upregulation in VSMC from OZR paralleled with increased ROS production, proliferation, and migration. HG increased PCSK9 expression in VSMC from LZR, but not in OZR, via oxidative stress and with effects reduced by PCSK9 inhibitors. These findings suggest that a dysregulation of PCSK9 in VSMC could be involved in vascular damage in metabolic disorders, such as obesity and diabetes.
Keywords: proprotein convertase subtilisin/kexin type 9; vascular smooth muscle cells; insulin-resistance; high glucose; zucker rat proprotein convertase subtilisin/kexin type 9; vascular smooth muscle cells; insulin-resistance; high glucose; zucker rat

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MDPI and ACS Style

Barale, C.; Tempesta, G.; Melchionda, E.; Morotti, A.; Frascaroli, C.; Danzero, A.C.; Femminò, S.; Penna, C.; Russo, I. PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose. Int. J. Mol. Sci. 2025, 26, 1003. https://doi.org/10.3390/ijms26031003

AMA Style

Barale C, Tempesta G, Melchionda E, Morotti A, Frascaroli C, Danzero AC, Femminò S, Penna C, Russo I. PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose. International Journal of Molecular Sciences. 2025; 26(3):1003. https://doi.org/10.3390/ijms26031003

Chicago/Turabian Style

Barale, Cristina, Giulia Tempesta, Elena Melchionda, Alessandro Morotti, Chiara Frascaroli, Alice Costanza Danzero, Saveria Femminò, Claudia Penna, and Isabella Russo. 2025. "PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose" International Journal of Molecular Sciences 26, no. 3: 1003. https://doi.org/10.3390/ijms26031003

APA Style

Barale, C., Tempesta, G., Melchionda, E., Morotti, A., Frascaroli, C., Danzero, A. C., Femminò, S., Penna, C., & Russo, I. (2025). PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose. International Journal of Molecular Sciences, 26(3), 1003. https://doi.org/10.3390/ijms26031003

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