Nitrite Regulates Mitochondrial Dynamics to Inhibit Vascular Smooth Muscle Cell Proliferation and Restenosis

Nitrite, a dietary constituent and endogenous signaling molecule previously thought to be a biologically inert product of endogenous nitric oxide oxidation, has recently been shown to regulate a myriad of biological processes. For example, nitrite has been shown to inhibit smooth muscle proliferation and attenuate restenosis after vascular injury. However, the mechanism of nitrite-dependent inhibition of smooth muscle proliferation remains elusive. Nitrite is an established regulator of mitochondrial morphology and function, and mitochondrial dynamics, the active formation (fusion) or fragmentation (fission) of cellular mitochondrial networks, has been previously shown to regulate cell cycle progression. Thus, we hypothesized that nitrite modulates mitochondrial dynamics and function to inhibit cell cycle progression and attenuate smooth muscle cell proliferation. Using rat aortic smooth muscle cells (RASMCs) we demonstrate that nitrite inhibits RASMC proliferation induced by platelet derived growth factor (PDGF) in a concentration dependent manner. This phenomenon is associated with mitochondrial fusion dependent on the upregulation of mitofusin-1 (Mfn1). Further, nitrite treatment upregulates the cyclin dependent kinase inhibitor p21, an effect that is abolished in Mfn1 deficient RASMCs. Ongoing studies are focused on determining the mechanism by which nitrite upregulates Mfn1 thereby stimulating mitochondrial fusion while increasing p21 expression. These data have important implications for dietary and pharmacological modulation of vascular health and uncover a novel potential physiological mechanism for the regulation of smooth muscle cell number.