Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption

Abstract

In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development.

The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

“…4,5 It was documented that activation of ERK and NF-kB signalling pathways is associated with increased activity of MMP2 and MMP9 in vascular smooth muscle cells and in aneurysmal tissue during AAA progression. 26,27 The increased activity of pro-inflammatory signalling pathways and protease activity in aneurysmal wall may, in turn, influence thrombus formation. Another protein that influences the activity of MMPs is NGAL.…”

Murine ultrasound-guided transabdominal para-aortic injections of self-assembling type I collagen oligomers

“…Current therapeutic strategies have focused on reducing extracellular matrix degradation and chronic inflammation (12,13), both of which are known to be important pathological features of AAAs (14). While most previous preclinical AAA work has administered experimental cell-based and pharmaceutical therapeutics through intraperitoneal injections (15), intravenous injections (16), or the animals' drinking water (17), minimally invasive injection strategies have the potential to locally deliver therapies with a clear translational potential (18). …”

The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm

“…The heparin binding domain of kallistatin is considered important for these functions [32,33,34]. Evidence from pre-clinical studies suggests that reducing inflammation [35], decreasing oxidative stress [36,37] and inhibiting angiogenesis [38] may limit AAA progression. Hence, in clinical management of AAAs, treatments targeting these mechanisms are considered to have potential benefits in managing AAAs [39].…”