Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats

Abstract

Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-β (TGF-β) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-β expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. The study supports an important role for AGE-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM.

Upregulated 14‑3‑3β aggravates restenosis by promoting cell migration following vascular injury in diabetic rats with elevated levels of free fatty acids

“…Non-invasive ultrasonographic imaging technology was used to evaluate the carotid artery wall thickness prior to carotid artery injury and 14 days following injury. consistent with the findings of a previous study (24), the level of carotid artery-stenosis was increased significantly in the high-FFA diabetic group, compared with that in the normal, diabetic, and high-fat diet groups (Fig. 2B).…”

The systolic–diastolic difference in carotid stiffness is increased in type 2 diabetes

“…Nonetheless, the higher prevalence of calcified peripheral arteries in T2D [33] may reflect increased elastin degradation in T2D. With regard to increased collagen crosslinking, it has been hypothesized that this is particularly driven by the formation of AGEs in T2D [10,12,13,15,34,35]. In our study however, further adjustment for SAF or the plasma AGEs -pentosidine, CML and CEL -did not materially alter our results.…”

Cardiometabolic Changes in Sirtuin1-Heterozygous Mice on High-Fat Diet and Melatonin Supplementation

“…In contrast, fibrosis was undetectable in WT mice on a lard-based diet for 16 weeks. This finding is because more prolonged dietary treatment, for almost 30 weeks, is necessary to obtain overt cardiac remodeling in obese mice [71,72]. However, a prolonged lard diet for over…”