Promising mechanism to prevent progression of AAA

PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysm in Mice

Er-shun Liand et al.

The natural history of AAA development is characterized by progressive vascular wall degeneration, thinning of collagen in the media, and elastin fragmentation and degradation. Several experimental models have assessed the role of extracellular matrix-degrading proteinases, proinflammatory mediators, Angiotensin II, VEGF [vascular endothelial growth factor], and TGFβ [transforming growth factor β]), and of numerus molecules  in AAA formation. To date pharmacological strategies targeting these molecules have been disappointing and new research is ongoing.

Liang et al have suggested a role for a novel pathway influencing the development of AAA in mice, involving the PARP-1 (poly[ADP-ribose] polymerase-1), a member of the nuclear enzymes family. PARP-1 is a DNA damage sensor, aimed to repair DNA and maintain genomic stability.

However, when PARP-1 is overactived by oxidative stress, it consumes ATP and leading to energy substrate depletion and to cell death; it interacts with proinflammatory transcription factors, promoting increased expression of cytokines, chemokines, adhesion molecules, and inflammatory mediators; all these actions seem to be more relevant in acute conditions.

The study of Liang et al was aimed to test whether PARP inhibition could prevent the formation of AAA. They have conducted 2 experimental studies: 1) in the first in vivo study AAA was induced by Angiotensin II infusion for 28 days in ApoE-/- mice and 2) in the second study  aortic endothelial cells and smooth muscle cells were evaluated after stimulation with Angiotensin  II for 24 hours.

Angiotensin II infusion in apoE-/- mice increased PARP-1 expression and activity and induced AAA formation, which was significantly reduced in the presence of genetic deletion of PARP-1. In animals with a genetic deletion of PARP-1 macrophage infiltration, intercellular and vascular adhesion molecules expression, matrix metalloproteinase expression and activity were all reduced, but the content in smooth muscle cells content and collagens expression in AAA ws increased.  The administration PJ-34, a potent, cell permeable and dose dependent inhibitor of PARP-1, produced the same results.

In aortic endothelial cells, Angiotensin II–induced oxidative stress and DNA damage increased PARP-1 expression and activity. Compared with the control, Angiotensin II increased TNF-α and IL-6 secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition reduced the inflammatory response.

In smooth muscle cells, Angiotensin II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression.

These results of in vivo and in vitro studies suggest that PARP-1 inhibition might be a feasible vasoprotective strategy for the prevention of AAA development, partially by reducing inflammation and decreasing the redox-dependent signaling, but not for the treatment of AAA once it is already developed.