A Novel Histone Deacetylase Inhibitor Reduces Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice

Abstract

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 expressionand AAA incidence suggesting this compound may warrant further investigation in the context of AAA biology.

Emerging Epigenetic Therapy for Vascular Proliferative Diseases

“…Thus, the acetylation status of the chromatin associated with particular genes is dictated by the balance between the activities of HATs and HDACs. These enzymes are shown to regulate expression of genes associated with various cellular processes like inflammation, proliferation and matrix modulation (Cao et al, 2005;Pons et www.intechopen.com al., 2009;Sahar et al, 2007;Vinh et al, 2008;Waltregny et al, 2005;Xu et al, 2007;Yan et al, 2009). HATs and HDACs are also recruited to gene promoters by multiprotein transcriptional complexes, where they regulate transcription through chromatin modification without directly binding the DNA.…”

The role of the renin-angiotensin system in aortic aneurysmal diseases

“…Chronic subcutaneous Ang II infusion into male apolipoprotein (apo) E -/-or low-density lipoprotein (LDL)-receptor -/-mice has consistently led to generation of pronounced AAAs in the suprarenal aorta [5][6][7][8][9][10][11][12]13••, [14][15][16]. Ang II infusion also induces AAAs of similar gross appearance in normolipidemic mice, although with a lesser incidence [17].…”

“…Another pharmacologic approach for reducing MMP activity has been to inhibit histone deacetylase. One such inhibitor, metacept, reduced Ang II-induced AAAs in male apoE -/-mice [16]. Both studies used inhibitors that are nonselective for specific MMPs and have the potential for effects on non-MMP targets.…”

Cardiovascular Diseases

“…At this junction, it appears that a combination of a specific class II HDAC agonist and a specific class I HDACi would be indicated for treatment of cardiac hypertrophy if toxicities are not compounded. HDACi have also been reported to inhibit atrial arrhythmia and abdominal aortic aneurysm (Vinh et al, 2008). Taken together, it appears that targeting HDACs may be indicated for the treatment of CVD.…”