Figure 8. Proposed actions of Necrostatin-1 and its optimized form Nec-1s during the development and progression of abdominal aortic aneurysm.

The common features of aneurysms– cell-death, inflammation and degradation of the extracellular matrix– are depicted in the vessel wall that consists of the intima, media and adventitia. VSMC in the media undergo apoptosis, primary or secondary (post-apoptotic) necrosis causing the release of DAMPs that subsequently stimulate inflammation. Nec-1/Nec-1s prevents apoptosis and necrosis, thereby reducing inflammation indirectly. Nec-1/Nec-1s may also directly reduce inflammation by preventing monocyte migration, inflammasome formation and increasing monocyte to M2 macrophage differentiation. Nec-1/Nec-1s may also promote tissue-repair through rescuing the reduction in the tropoelastin and LOX normally observed in the stressed VSMCs and therefore preserve extracellular matrix. Red arrows depict inhibition whereas green arrows show activation. VSMC: vascular smooth muscle cell, DAMP: damage-associated molecular patterns, LOX: lysyl oxidase, MCP-1: monocyte chemoattractant protein-1, TNFα: tumor necrosis factor alpha.