Abstract 13927: Allosteric Activation of PP2A Inhibits Experimental Abdominal Aortic Aneurysm

Abstract

Introduction: In abdominal aortic aneurysms (AAA), recent studies strongly implicate the kinase, Mitogen-activated protein kinase (MAPK) as an essential contributor to its pathogenesis. Upregulation of Protein phosphatase 2A (PP2A) activity has been shown to be of significant therapeutic value, however pharmaceutically tractable approaches to directly activate PP2A remain elusive in AAA disease. Hypothesis: In light of the potential phosphatase effects PP2A can exert on MAPK protein targets, we hypothesized that PP2A activation by small molecule activators of PP2A (SMAPs) might mitigate AAA progression. Methods: Oral administration of the small molecule activator of PP2A, termed DT-1154, was performed for 4 weeks in apolipoprotein E-null (ApoE-/-) mice concomitant with subcutaneous Angiotensin II infusion. Human abdominal artery tissue as well as abdominal artery tissue from Ang II-infused ApoE-/- mice (+/- DT-1154) were examined by PCR, Western blotting and IHC. Results: To examine its activation state, Phosphorylated-PP2A (Y307) was stained in human and murine AAA tissues, with an increased phospho-PP2A signal indicating less cellular phosphatase activity. Examination of these tissues indeed revealed increased phosphorylation of PP2A compared to control non-AAA tissues indicating a marked reduction of PP2A activation. This strongly suggests that compromised PP2A activation can drive AAA formation. Oral administration of DT-1154 also resulted in significantly reduced AAA incidence and aortic dilation in these pro-AAA ApoE-/- mice. Finally, mechanistic studies indicated that blockade of ERK1/2 and NF-kB signaling by DT-1154 contributed to its effects in ameliorating AAA progression. Conclusions: These studies demonstrate a role of PP2A in AAA etiology and implicate that activation of PP2A may serve as a novel strategy to limit human AAA progression.