Deficiency of p27kip1, a Cyclin-Dependent Kinase Inhibitor, Accelerates Topical Elastase/3-Aminopropionitrile Fumarate Salt-Induced Abdominal Aortic Aneurysm Development in Mice

Abstract

<p>Introduction: Abdominal aortic aneurysm (AAA) is a multifactorial disease with limited identification of contributing genetic factors. p27kip, also known as CDKN1B, is a cell cycle inhibitor that regulates vascular smooth muscle cells (VSMCs) and macrophages (Mϕ). The role of p27 in AAA development was assessed by AAA induction in p27 knockout (p27-/-) and wild-type (WT) mice.

Methods: AAAs were induced in male and female p27-/- and WT mice via topical elastase with oral administration of 3-aminopropionitrile fumarate salt. Aortic diameter was measured with ultrasound. VSMCs and macrophages were quantified by immunohistochemistry. Oxidative stress genes were analyzed using polymerase chain reaction. In vitro cell proliferation, migration, and oxidative stress assay were performed on VSMCs isolated from abdominal aortas.

Results: p27-/- mice developed significantly larger AAA diameter than WT mice with reduced VSMCs and increased macrophages. M1ϕ were significantly elevated in p27-/- mice, while M2ϕ were more abundant in WT mice. p27-/- mice had lower expression of the antioxidant gene, Nrf2. In vitro experiments demonstrated increased proliferation and migration in p27-/- cells with increased oxidative stress sensitivity.

Conclusion: Knockout of p27 accelerated aneurysm growth with increased macrophage infiltration, VSMC loss, and decreased antioxidant factors, highlighting a potential role for p27 in AAA progression. </p>.

Keywords: Abdominal aortic aneurysm; Macrophage infiltration; Oxidative stress; Vascular smooth muscle cell apoptosis; p27kip.