An, Wenxi
(2024)
Mitofusin 1-dependent Regulation of Mitochondrial Redox and Energetic Function Modulates Vascular Smooth Muscle Cell Phenotype and Proliferation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Atherosclerosis is characterized by compromised vessel reactivity, intimal hyperplasia, and inflammation and underlies most major cardiovascular complications. While balloon angioplasty has over a 90% initial success rate to restore vascular function, 10% to 20% of these patients exhibit restenosis. Vascular smooth muscle cell (VSMC) dysfunction is a major driver of restenosis. In response to vascular injury, VSMC lose their contractile function and migrate to the intimal layer of the vessel, where they aberrantly proliferate to potentiate intimal hyperplasia. Nitrite, an endogenous oxidation product of nitric oxide known to regulate mitochondrial dynamics and function, has also been shown to attenuate intimal hyperplasia after carotid balloon injury. However, the mechanism by which nitrite regulates VSMC proliferation and contractile function is not known. Prior studies associate changes in mitochondrial fusion and fission (dynamics) with alterations in VSMC proliferation and function. Therefore, we hypothesized that nitrite modulates mitochondrial dynamics to inhibit VSMC proliferation, leading to attenuation of intimal hyperplasia. We demonstrate that nitrite inhibits proliferation of rat aortic smooth muscle cells (RASMC) by promoting mitochondrial fusion through the upregulation of mitofusin 1 (Mfn1), a GTPase that catalyzes mitochondrial fusion. We show that silencing Mfn1 in RASMC decreases cellular ATP production and enhances cellular oxidant production which increases RASMC proliferation and downregulates contractile gene expression. To further elucidate the role of the nitrite/Mfn1 signaling pathway in vivo, SMC-specific Mfn1 knockout mice were generated and subjected to carotid ligation injury to induce intimal hyperplasia. Compared to wildtype mice, SMC-specific Mfn1 knockout mice showed exacerbated intimal hyperplasia consistent with a role for Mfn1 in maintaining VSMC function. While oral administration of nitrite attenuated intimal hyperplasia in wildtype mice, it did not have a significant effect in Mfn1 knockout mice, consistent with in vitro data showing that the anti-proliferative effect of nitrite is Mfn1-dependent. Collectively, the data presented here demonstrate that nitrite-mediated Mfn1 upregulation regulates VSMC function by modulating mitochondrial redox function. These results will be discussed in the context of the therapeutic effects of nitrite and the role of Mfn1 as a potential therapeutic target to attenuate VSMC dysfunction in pathologic vascular remodeling.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
2 July 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
15 July 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
124 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cardiovascular diseases, restenosis, vascular smooth muscle cells, proliferation, redox |
| Date Deposited: |
14 Oct 2024 14:33 |
| Last Modified: |
14 Oct 2024 14:33 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46684 |
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