Key result
Nitrite attenuates intimal hyperplasia and VSMC proliferation in mice by inhibiting mitofusin-1 degradation.
Why the study?
Nitrite attenuates intimal hyperplasia after vascular injury, but the underlying mechanisms remain incompletely understood.
Does nitrite prevent intimal hyperplasia and vascular smooth muscle cell proliferation in models of vascular injury?
Does nitrite prevent intimal hyperplasia and vascular smooth muscle cell proliferation in models of vascular injury?
Nitrite attenuates restenosis and intimal hyperplasia by inhibiting MARCH5-mediated degradation of Mfn1, highlighting a novel mechanism for its vasoprotective effects.
Should not yet change post-stent care; leaves open nitrite's therapeutic potential to limit IH via redox mechanisms.
Vascular disease remains a leading cause of morbidity and mortality and is driven by maladaptive vascular remodeling following injury. Stent-induced vascular injury induces vascular smooth muscle cell (VSMC) phenotypic switching from a contractile to a proliferative state, resulting in intimal hyperplasia (IH), restenosis and compromised vessel function. Nitrite, an endogenous oxidation product of nitric oxide and a dietary constituent, attenuates IH after vascular injury; however, its underlying mechanisms remain incompletely understood. Nitrite is known to modulate mitochondrial structure and function, and dysregulated mitochondrial dynamics have independently been implicated in VSMC proliferation. We therefore hypothesized that nitrite attenuates IH by modulating mitochondrial dynamics to suppress VSMC proliferation. Using rat aortic smooth muscle cells (RASMCs), we demonstrate that nitrite treatment inhibits cell cycle progression and cell proliferation through upregulation of mitofusin-1 (Mfn1), a GTPase that catalyzes mitochondrial fusion. Mechanistically, nitrite increased Mfn1 protein levels by inhibiting Mfn1 proteasomal degradation. Mfn1 deletion resulted in enhanced proliferation, loss of contractile gene expression, and decreased expression of antioxidant enzymes including catalase and glutathione peroxidase. Restoration of cellular antioxidant capacity significantly attenuated proliferation and preserved contractile gene expression in Mfn1-deficient cells. Smooth muscle cell–specific Mfn1 knockout mice subjected to carotid artery ligation injury exhibited exacerbated IH compared to wildtype mice. Nitrite administration significantly decreased IH in wildtype mice but not Mfn1-deficient mice. These findings identify endogenous Mfn1 as a critical regulator of VSMC cell cycle progression and as an essential mediator of the vasoprotective effects of nitrite. The deletion of MFN1 causes the downregulation of catalase and glutathione peroxidase, which in turn leads to ROS-dependent smooth muscle cell proliferation in vitro and exacerbation of intimal hyperplasia in vivo. Nitrite inhibits the E3-ligase MARCH5, which decreases MFN1 degradation and thus prevents smooth muscle cell proliferation in vitro and intimal hyperplasia in vivo. • Nitrite inhibits vascular smooth muscle cell proliferation by increasing mitofusin-1 levels • Mfn1 loss causes ROS production leading to smooth muscle cell proliferation/phenotype switch. • Nitrite attenuates restenosis in wildtype mice but not mice deficient in smooth muscle cell Mfn1.
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An et al. (2026) studied this question. Nitrite attenuates intimal hyperplasia and vascular smooth muscle cell proliferation by inhibiting the degradation of mitofusin-1, an effect lost in mitofusin-1-deficient mice.
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