Medial artery calcification (MAC) is common in patients with type 2 diabetes mellitus (T2DM) and end-stage renal disease (CKD5). Low-grade arterial inflammation is common to both conditions, and elevated levels of TNF-α have been reported in both DM and CKD5. We hypothesized that TNF-α may play a role in the MAC of T2DM. Therefore, we studied the effects of inhibiting TNF-α in male LDLR−/− mice fed high-fat diabetogenic diets (HFD)-a model of T2DM and aortic vascular calcification. Four-week-old LDLR−/− mice were fed either normal mouse chow (CHOW; n = 5), HFD with twice-weekly sc vehicle injection (HFD + VEH; n = 10), or HFD with twice-weekly sc infliximab injection (HFD + INX at 10 mg/kg; n = 10). Animals were sacrificed after 4 weeks; serum, aorta, and heart were harvested for analysis. Animals fed an HFD exhibited hyperglycemia, hyperlipidemia, and hyperleptinemia, with significantly increased levels of TNF-α; moreover, markers of inflammation and oxidative stress, viz., haptoglobin and 8-F isoprostane (IsoP), were concomitantly up-regulated. Injection with infliximab did not prevent HFD-induced hyperglycemia, hyperlipidemia, or hyperleptinemia; however, both haptoglobin and IsoP induction were inhibited by infliximab treatment. HFD-induced T2DM up-regulated osteogenic BMP2-Msx2-Wnt signaling in the aorta. Compared with the HFD + VEH group, aortic BMP2-Msx2-Wnt signaling was significantly attenuated in the HFD + INX group, to a level that approximated that of the CHOW animals; aortic BMP2, Msx2, Wnt3a, and Wnt7a were down-regulated by infliximab. Next, we generated transgenic mice that overexpress TNF-α in the vascular smooth muscle of large arteries (SM22-TNF-α transgenics). Compared with wild-type siblings, SM22-TNF-α transgenic mice had marked up-regulation of the ostegonic BMP2, Msx2, Wnt3a, and Wnt7a signals in the aorta. Finally, HFD-induced aortic calcium content was significantly reduced by infliximab treatment (1.44 0.19 vs 1.00 0.07 g calcium/mg dry aortic weight; p = .03, two-tailed t-test). Thus, in this model of T2DM, diet-induced inflammation, oxidative stress, aortic BMP2-Msx2-Wnt signaling, and vascular calcification are regulated by TNF-α. TNF-α-dependent low-grade vascular inflammation may represent the mechanistic link for the remarkable similarities in phenotype and histopathology of MAC in T2DM and CKD5.
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