Aluminum Chloride Pretreatment of Elastin Inhibits Elastolysis by Matrix Metalloproteinases and Leads to Inhibition of Elastin-Oriented Calcification

Abstract

Calcification of elastin occurs in many pathological cardiovascular diseases including atherosclerosis. We have previously shown that purified elastin when subdermally implanted in rats undergoes severe calcification and aluminum chloride (AlCl(3)) pretreatment of elastin inhibits calcification. In the present study we investigated whether matrix metalloproteinase (MMP) binding to elastin and elastin degradation is prevented by AlCl(3) pretreatment. Subdermal implantation of AlCl(3)-pretreated elastin showed significantly lower MMP-9 and MMP-2 activity surrounding the implant as compared to the control implants. AlCl(3) pretreatment also significantly inhibited elastin implant calcification at the seven-day implant period (AlCl(3)-pretreated 4.07 +/- 1.27, control 23.82 +/- 2.24 microg/mg; p<0.0001). Moreover, elastin gel zymography studies showed that gel pretreatment with AlCl(3) inhibited elastolysis by MMP-9. We also demonstrate significant suppression of MMP-2 activity in aortic wall segments of AlCl(3)-pretreated porcine bioprosthetic heart valve implants as compared to control valve implants in sheep mitral valve replacement studies. AlCl(3) pretreatment also significantly inhibited calcification of elastin in this model. Thus, we conclude that aluminum ion binding to elastin prevents MMP-mediated elastolysis and thus prevents elastin calcification.

Association of Bone Activity, Calcium Load, Aortic Stiffness, and Calcifications in ESRD

“…The data published to date do not favor a possible association between Al and aortic stiffness or AoCS, because elastin calcifications and elastolysis by matrix metalloproteinases are prevented by Al chloride. 22,23 Furthermore, several patients with active bone, including those without AoC, had received Al-containing PO 4 binders (Figure 3). The principal novelty of this study concerns the relationships between Ca load, bone activity, and aortic stiffness.…”

Elastin Degradation and Calcification in an Abdominal Aorta Injury Model

“…6 Moreover, we have shown that treatment of elastin with aluminum ions before implantation completely abolished elastin calcification by mechanisms that include inhibition of elastolysis by MMPs. 7 These results strongly point to a direct correlation between elastin degradation and calcification. To study mechanisms of elastin calcification in a clinically relevant circulatory model, we adapted an arterial injury model that involves a single periarterial application of a calcium chloride (CaCl 2 ) solution.…”

Mechanobiology in the Third Dimension

“…2. Gels can also be made from elastin, although these are typically used for zymography; 8 fibronectin, 195 which is used as a coating for 2D cell attachment or as a supplement to collagen gels; and hyaluronan, 45 which is often used in in vitro studies of cell-cartilage interactions. Alginate, a naturally occurring polysaccharide, forms a gel when divalent cations are added to the aqueous sodium alginate solution and is often used to study chondrocyte behavior; 83 since it is minimally adhesive for cells, it often has RGD binding sequences added to create a scaffold with specifically selected adhesion properties.…”