Effect of Pregnancy Associated Plasma Protein- A Overexpression on Athero- sclerotic Plaque Morphology in Mice

Objective: A novel metalloproteinase, Pregnancy Associated Plasma Protein-A (PAPP-A), has been implicated in the development of atherosclerosis, and is under consideration as a novel biomarker for acute coronary syndrome and unstable plaque. The aim of this study was to determine if PAPP-A overexpression directly contributes to plaque vulnerability. Methods: Apolipoprotein E knock-out (ApoE KO) mice, a model of atherosclerotic development, and ApoE KO mice overexpressing PAPP-A transgene in arterial smooth muscle (ApoE KO/Tg) were fed a high fat diet for 20 or 40 weeks starting at seven weeks of age. At harvest, the brachiocephalic artery (BCA) was fixed, embedded in paraffin, sectioned and stained for morphologic analyses. Results: After 20 weeks on high fat diet, significantly more ApoE KO/Tg mice had BCA lesions with a necrotic core and fibrous cap than did ApoE KO mice. After 40 weeks on high fat diet all mice had BCA plaques with necrotic cores, but plaque progression with healed ruptures (i.e., buried fibrous caps), and plaque inflammation were greater in BCA of ApoE KO/Tg mice than in ApoE KO mice. Conclusion: Overexpression of PAPP-A in arterial smooth muscle of ApoE KO mice is associated with accelerated plaque progression and development of vulnerable and ruptured plaque.