Vanin-1 Pantetheinase Drives Smooth Muscle Cell Activation in Post-Arterial Injury Neointimal Hyperplasia

Abstract

The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1 −/− SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1−/− mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization.

Tumor Necrosis Factor-α Induces Aortic Intima-Media Thickening via Perivascular Adipose Tissue Inflammation

“…2i-l). Moreover, Ki-67, a marker for cell proliferation [9,13] was also significantly increased in the aorta of TNF-α-injected mice compared to controls (fig. 2m-p).…”

“…Expression of TGF-β1, MMP-2, α-SMA and Ki-67 in PVAT and the aorta was examined using anti-mouse TGF-β1 (1:50), MMP-2 (1:50), α-SMA (1:6,400) and Ki-67 antibodies following previously described immunohistochemical (IHC) methods [11,12,13]. Images were analyzed using Image Pro Plus software 6.0 and signal intensities quantified in a blinded fashion in 5-7 randomly chosen fields on ≥3 sections for each animal.…”

Vanin-1 Is a Key Activator for Hepatic Gluconeogenesis

“…For example, VNN1-deficient mice are resistant to intestinal inflammation, oxidative stress, and experimental colitis (15,16). VNN1 also plays a critical role in malaria susceptibility, psoriasis, carcinogenesis, and cardiovascular disease (29)(30)(31)(32). Importantly, the vnn1 gene is one of the major targets of PPARa in the mouse liver, which strongly implies that VNN1 is involved in the regulation of energy metabolism (18).…”

Pharmacological Inhibition of Vanin Activity Attenuates Transplant Vasculopathy in Rat Aortic Allografts

“…9,15 VNN1 knockout mice show higher PPARγ levels in vitro and less NI formation to carotid artery ligation in vivo. 16 The pathogenesis of TV, however, is different from the vascular injury in the model used in that study; therefore, the pathophysiological role of vanin cannot be directly extrapolated to TV.…”