PPAR-Gamma Activation May Inhibit the In Vivo Degeneration of Bioprosthetic Aortic and Aortic Valve Grafts under Diabetic Conditions.

Shintaro Katahira,Yukiharu Sugimura,Jessica Isabel Selig,Mareike Barth,Sophia Grupp,Payam Akhyari,Robin Doepp,Artur Lichtenberg

doi:10.3390/ijms222011081

Abstract

Background: We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). Methods: DM was induced in male Wistar rats by high-fat diet with an intraperitoneal streptozotocin (STZ) injection. The experimental group received additional pioglitazone, and controls received normal chow without STZ (n = 20 each group). Cryopreserved aortic donor grafts including the aortic valve were analyzed after 4 weeks and 12 weeks in vivo for analysis of calcific bioprosthetic degeneration. Results: DM led to a significant media proliferation at 4 weeks. The additional administration of pioglitazone significantly increased circulating adiponectin levels and significantly reduced media thickness at 4 and 12 weeks, respectively (p = 0.0002 and p = 0.0107, respectively). Graft media calcification was highly significantly inhibited by pioglitazone after 12 weeks (p = 0.0079). Gene-expression analysis revealed a significant reduction in relevant chondro-osteogenic markers osteopontin and RUNX-2 by pioglitazone at 4 weeks. Conclusions: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM.

Highlights

Diabetes mellitus has been identified as a risk factor for the development of calcific aortic valve disease (CAVD) [1,2]
Blood glucose levels were significantly higher in both groups with diabetic conditions (DM, diabetes mellitus (DM)+Pio) at both time points of 4 weeks and 12 weeks as compared to the start of the experiments
Plasma analysis revealed that total cholesterol, triglycerides, and high-density lipoprotein (HDL) at 4 weeks were significantly higher in the DM group than in the control group

Summary

Introduction

Diabetes mellitus has been identified as a risk factor for the development of calcific aortic valve disease (CAVD) [1,2]. With respect to heart valve prostheses, biological solutions omitting lifelong anticoagulant therapy have been increasingly favored world-wide, despite durability limitations inherently associated with biological valvular prostheses In this context, diabetes has been reported as a risk factor for structural valve deterioration, which emphasizes the need for additive postoperative therapy measures to improve the durability of bioprosthetic valves, in young patients with diabetes. We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). Conclusions: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM

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