A novel histone deacetylase inhibitor reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice

Background/Aims: Aberrant expression of components of the matrix metalloproteinase ( MMP) enzyme system is implicated in abdominal aortic aneurysm ( AAA) formation. We aimed to investigate the influence of a novel histone deacetylase ( HDAC) inhibitor ( HDACi) metacept- 1 ( MCT- 1), previously documented to reduce MMP expression, on HDAC activity and MMP expression in aortic smooth muscle cells and the in vivo incidence of AAAs. Methods: Western blot and gelatin zymography were used to determine HDAC activity and MMP- 2 expression and activity in rat ( rVSMCs) and human aortic vascular smooth muscle cells ( hVSMCs) in vitro. In vivo AAAs were generated using apolipoprotein E-deficient mice infused with angiotensin ( Ang) II. Immunohistochemistry detected MMP- 2 and - 9 expression in AAA tissue samples. Results: In vitro, MCT- 1 inhibited HDAC activity in rVSMCs, and MMP- 2 expression and proteolytic activity in hVSMCs. In vivo, Ang II treatment alone exhibited an AAA incidence of 84%. Doxycycline decreased the incidence of AAAs to 50%. Importantly, MCT- 1 reduced AAA incidence to approximately 44%. MMP- 2 and - 9 immunoreactivity was reduced in MCT-1-treated aortic tissue. Conclusion: The novel HDACi MCT-1 inhibits MMP expression and AAA incidence suggesting this compound may warrant further investigation in the context of AAA biology.