Increased Expression of Nox1 in Neointimal Smooth Muscle Cells Promotes Activation of Matrix Metalloproteinase-9

Abstract

Objective: Vascular injury causes neointimal hypertrophy, which is characterized by redox-mediated matrix degradation and smooth muscle cell (SMC) migration and proliferation. We hypothesized that, as compared to the adjacent medial SMCs, neointimal SMCs produce increased superoxide via NADPH oxidase, which induces redox-sensitive intracellular signaling to activate matrix metalloproteinase-9 (MMP-9). Methods and Results: Two weeks after balloon injury, rat aorta developed a prominent neointima, containing increased expression of NADPH oxidase and reactive oxygen species (ROS) as compared to the medial layer. Next, SMCs were isolated from either the neointima or the media and studied in culture. Neointimal-derived SMCs exhibited increased Nox1 expression and ROS levels as compared to medial SMCs. Neointimal SMCs had higher cell growth rates than medial SMCs. ROS-dependent ERK1/2 phosphorylation was greater in neointimal SMCs. MMP-9 activity, as detected by gel zymography, was greater in neointimal SMCs under resting and stimulated conditions and was prevented by expression of an antisense to Nox1 or treatment with an ERK1/2 inhibitor. Conclusions: Following vascular injury, the increased expression of Nox1 in SMCs within the neointima initiates redox-dependent phosphorylation of ERK1/2 and subsequent MMP-9 activation.

Reactive Oxygen Species Generation and Atherosclerosis

“…65 Furthermore, expression of Nox1 was higher in neointimal SMCs than in normal medial cells. 66 Elevated levels of Nox1 were associated with ERK1/2 (extracellular signal-regulated kinases 1/2) activation and enhanced MMP-9 (matrix metallopeptidase 9). 66 Importantly, Nox1 forms canonical or hybrid systems with p47 phox in place of NoxO1 in the hybrid system.…”

“…66 Elevated levels of Nox1 were associated with ERK1/2 (extracellular signal-regulated kinases 1/2) activation and enhanced MMP-9 (matrix metallopeptidase 9). 66 Importantly, Nox1 forms canonical or hybrid systems with p47 phox in place of NoxO1 in the hybrid system. Production of superoxide by hybrid Nox1 is regulated by ezrin-radixinmoesin-binding phosphoprotein 50 (EBP50).…”

Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling

“…With regard to the increased migration of MCT-PASMC, we screened for the expression and/or phosphorylation of p21-activated protein kinase-1 (PAK1), cofilin, and matrix metalloproteinase-9 (MMP-9), which have been described as potential downstream targets of Nox1 with regard to migration (36,69,89,94,95). MCT treatment resulted in an increased cofilin phosphorylation (Fig.…”

c-Jun N-terminal kinase attenuates TNFα signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells

“…The critical role of Nox1 is demonstrated by the fact that VSMC proliferation and migration are reduced in Nox1 null cells and Nox1 plays a critical role in neointimal formation by supporting these events as well as extracellular matrix production [25]. Increased expression of Nox1 is observed in neointimal VSMCs where it promotes activation of matrix metalloproteinase-9 [26]. Furthermore, Nox1 overexpression potentiates vascular smooth muscle hypertrophy in transgenic mice [27].…”