Background: Abdominal aortic aneurysms (AAA) are characterized by the loss of contractile smooth muscle cells (SMCs) as a result of cell death and SMC dedifferentiation. Therefore, pharmacological interventions should aim to increase the number of SMCs in the diseased aortic wall. The catalytic class IA PI 3-kinase isoform p110α is a key regulator of cell proliferation and survival in numerous cell types. Herein, we characterized the impact of a novel p110α activator on SMC proliferation and investigated the role of p110α in AAA development and progression.
Methods: The effects of the pharmacological p110α activator #1938 and the specific Forkhead-box O1 (FOXO1) inhibitor AS1842856 on SMC proliferation and migration were investigated by standard techniques. Downstream signaling pathways were analyzed by Western blotting. To investigate the impact of p110α on AAA formation and progression, AAA was induced in sm-p110α-/- mice lacking p110α in SMCs as well as in wild-type control mice. Phenotypic changes in aortas were examined by ultrasound, immunohistochemistry, and histochemistry.
Results: Activation of p110α with 10µM #1938 induced proliferation (2.91±0.84-fold increase, p<0.05) and migration (1.81±0.17 fold increase, p<0.05) of wild-type SMCs, but not of p110α-/- SMCs (1.11±0.34 (proliferation) and 1.29±0.25 (migration)). Western blot analyses of downstream signal transduction cascades revealed that #1938 induces the phosphorylation/activation of AKT and the phosphorylation/inactivation of the transcription factor FOXO1. Inactivation of FOXO1 is essential for p110α-mediated SMC proliferation as the wild type phenotype could be completely rescued in p110α-deficient SMCs by specific inhibition of FOXO1. PPE treatment of sm-p110α-/- mice resulted in a significantly increased abdominal aortic diameter compared to wild-type controls (70.2±32.5% versus 42.4±18.9%, n=9-10, p<0.05). p110α was involved in the regeneration processes during AAA progression: while increased medial hypertrophy and cell proliferation were detected in the respective aortic segments of wild-type mice 28 days after PPE intervention, these processes were reduced in sm-p110α-/- aorta. In addition, elastic fibers in sm-p110α-/- aortas were characterized by more frequent elastic fiber breaks.
Conclusions: p110α activity in SMCs protects against the development and progression of AAA by inducing SMC proliferation during AAA progression. The novel p110α activator #1938 stimulates proliferation and migration of SMCs in vitro and therefore represents a potential pharmacological agent for stabilizing the aortic wall during AAA development and progression.
