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A role for peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists in counteracting the degeneration of cardiovascular grafts.
Journal of Cardiovascular Pharmacology  (IF3.105),  Pub Date : 2021-10-04, DOI: 10.1097/fjc.0000000000001150
Anna Kathrin Assmann, Daniel Goschmer, Yukiharu Sugimura, Agunda Chekhoeva, Mareike Barth, Alexander Assmann, Artur Lichtenberg, Payam Akhyari

Aortic valve replacement for severe stenosis is a standard procedure in cardiovascular medicine. However, the use of biological prostheses has limitations especially in young patients due to calcifying degeneration resulting in implant failure. Pioglitazone, a PPAR-gamma agonist, was shown to decrease the degeneration of native aortic valves. In this study, we aim to examine the impact of pioglitazone on inflammation and calcification of aortic valve conduits in a rat model.Cryopreserved aortic valve conduits (AoC) (n=40) were infrarenally implanted into Wistar rats treated with pioglitazone (75mg/kg chow; n=20, PIO) or untreated (n=20, controls). After 4 or 12 weeks, AoC were explanted and analyzed by histology, immunohistology and PCR.Pioglitazone significantly decreased the expression of inflammatory markers and reduced the macrophage-mediated inflammation in PIO compared to controls after 4 (p=0.03) and 12 weeks (p=0.012). Chondrogenic transformation was significantly decreased in PIO after 12 weeks (p=0.001). Calcification of the intima and media was significantly reduced after 12 weeks in PIO versus controls (intima: p=0.008; media: p=0.025). Moreover, echocardiography revealed significantly better functional outcome of the AoC in PIO after 12 weeks compared to control. Interestingly, significantly increased intima hyperplasia could be observed in PIO compared to controls after 12 weeks (p=0.017).Systemic PPAR-gamma activation prevents inflammation as well as intima and media calcification in aortic valve conduits, and seems to inhibit functional impairment of the implanted aortic valve. To further elucidate the therapeutic role of PPAR-gamma regulation for graft durability, translational studies and long-term follow-up data should be striven for.