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. Copyright (c) 2007 S. Karger AG, Basel.
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. Copyright (c) 2007 S. Karger AG, Basel.
Authors: Justin L Grodin; Tiffany M Powell-Wiley; Colby R Ayers; Darpan S Kumar; Anand Rohatgi; Amit Khera; Darren K McGuire; James A de Lemos; Sandeep R Das Journal: Vasc Med Date: 2011-10 Impact factor: 3.239
Authors: Debra L Rateri; Deborah A Howatt; Jessica J Moorleghen; Richard Charnigo; Lisa A Cassis; Alan Daugherty Journal: Am J Pathol Date: 2011-07-19 Impact factor: 4.307
Authors: Venkateswaran Subramanian; Jonathan Golledge; Elizabeth B Heywood; Dennis Bruemmer; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2011-11-17 Impact factor: 8.311