Abstract 443: Inhibition of TGFβ Attenuates Angiotensin II Effects to Increase Vascular Biglycan and Atherosclerosis
Background: Proteoglycans, a major component of extracellular matrix in the vascular wall, play a critical role in the development of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins. Of all the vascular proteoglycans, biglycan has been shown to be the one most closely associated with apolipoprotein B. Our previous studies showed that AngII increases vascular biglycan content and predisposes to diet-induced atherosclerosis in Ldlr null mice. Moreover, we demonstrated that TGFβ is required for AngII stimulation of vascular biglycan content in vitro. In this study, we determined whether TGFβ is required for AngII-induced biglycan accumulation and atherosclerosis predisposition in vivo.
Methods and Results: Ldlr null mice fed a normal chow diet were infused with AngII or saline for 28 days. TGFβ1 levels in AngII-infused mice peaked at 24h then returned to baseline levels by day 5. A single injection of TGFβ neutralizing antibody 1D11 (2mg/kg) not only prevented the induction of TGFβ1 levels by AngII, but also attenuated AngII-induced accumulation of aortic biglycan content, whereas there was no attenuation of AngII-induced increase in TGFβ or biglycan by a control antibody. To study atherosclerosis, the experiment was repeated but after 28 days of AngII or saline infusions the pumps were removed and the mice were fed Western diet for 6 weeks. TGFβ neutralizing antibody injection had no effect on systolic blood pressure or plasma lipids (triglyceride and cholesterol). However, AngII-infused mice that received TGFβ neutralizing antibody injection showed reduced atherosclerotic lesion area (aorta root, en face and the brachiocephalic artery) compared to AngII-infused mice that received a control antibody injection. Therefore, our study showed that TGFβ inhibition attenuates AngII stimulation of vascular biglycan content in vivo and attenuates AngII-accelerated atherosclerosis.
- © 2012 by American Heart Association, Inc.