Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture

Yue Shen,Hongyan Zhao,Michael A Seidman,Keerit Tauh,Bruce M Mcmanus,Cathy Turner ,Stephanie Sellers ,Matthew R Zeglinski,R Chris Bleackley,Yulia Merkulova,Stephanie Santacruz,Haishan Zeng,Lubos Bohunek,Valerio Russo,Zhengguo Wu,Tatjana Bozin,Erkki Ruoslahti,Tero A.h Järvinen ,Cameron Oram,David J Granville

doi:10.1038/s41598-017-16194-8

Abstract

Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.

Highlights

IntroductionThe anchorage to cells afforded by CAR peptide in CAR-DCN has substantially increased its biological activity and systemically administrated CAR-DCN accumulated in the neo-vasculature-rich wound granulation tissue in significantly larger quantities than native DCN17
CAR-DCN-treated, angiotensin II (Ang II)-infused Apolipoprotein E knockout (ApoE-KO) mice exhibited a significant increase in 28-day survival (92.8%, n = 14; vs 60%, n = 15; P = 0.035) in comparison to vehicle-treated controls (Fig. 1A)
To follow abdominal aortic aneurysm (AAA) progression, all mice were examined by ultrasound at three time points

Summary

Introduction

The anchorage to cells afforded by CAR peptide in CAR-DCN has substantially increased its biological activity and systemically administrated CAR-DCN accumulated in the neo-vasculature-rich wound granulation tissue in significantly larger quantities than native DCN17. CAR-DCN is substantially more active than the native DCN against TGF-β17 These features were associated with more rapid wound healing and suppressed scar formation when compared to improvement obtained by native DCN17. Based on our previous studies pertaining to the role of DCN in the development of AAA15, combined with the neo-vasculature- and inflammatory-homing characteristics of the CAR-DCN peptide prompted us to investigate whether systemic administration of CAR-DCN could affect the onset and progression of AAA. We hypothesized that systemically-administered CAR-DCN would attenuate AAA progression and rupture, and increase survival

Methods

Results

Conclusion