Inhibition of Receptor-Interacting Protein Kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model.

Abstract

Abdominal aortic aneurysm (AAA) is a common aortic disease with a progressive nature. There is no approved pharmacological treatment to effectively slow aneurysm growth or prevent rupture. Necroptosis is a form of programmed necrosis that is regulated by receptor-interacting protein kinases (RIPs). We have recently demonstrated that the lack of RIP3 in mice prevented aneurysm formation. The goal of the current study is to test whether perturbing necroptosis affects progression of existing aneurysm using the RIP1 inhibitors Necrostatin-1 (Nec-1) and an optimized form of Nec-1, 7-Cl-O-Nec-1 (Nec-1s). Seven days after aneurysm induction by elastase perfusion, mice were randomly administered DMSO, Nec-1 (3.2 mg/kg/day) and Nec-1s (1.6 mg/kg/day) via intraperitoneal injection. Upon sacrifice on day 14 postaneurysm induction, the aortic expansion in the Nec-1s group (64.12 ± 4.80%) was significantly smaller than that of the DMSO group (172.80 ± 13.68%) (P < 0.05). The mean aortic diameter of Nec-1 treated mice appeared to be smaller (121.60 ± 10.40%) than the DMSO group, though the difference was not statistically significant (P = 0.1). Histologically, the aortic structure of Nec-1s-treated mice appeared normal, with continuous and organized elastin laminae and abundant αActin-expressing SMCs. Moreover, Nect-1s treatment diminished macrophage infiltration and MMP9 accumulation and increased aortic levels of tropoelastin and lysyl oxidase. Together, our data suggest that pharmacological inhibition of necroptosis with Nec-1s stabilizes pre-existing aneurysms by diminishing inflammation and promoting connective tissue repair.

• Authors: Qiwei Wang, Ting Zhou, Zhenjie Liu, Jun Ren, Noel Phan, Kartik Gupta, Danielle M Stewart, Stephanie Morgan, Carmel Assa, K Craig Kent, Bo Liu
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 42159 (02 10 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28186202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cardiovascular Agents
• GTPase-Activating Proteins
• Imidazoles
• Indoles
• Ralbp1 protein, mouse
• Tropoelastin
• necrostatin-1
• Elastin
• Protein-Lysine 6-Oxidase
• Pancreatic Elastase
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Aortic Aneurysm, Abdominal (chemically induced, drug therapy, genetics, pathology)
• Apoptosis (drug effects)
• Cardiovascular Agents (pharmacology)
• Cell Movement (drug effects)
• Disease Models, Animal
• Elastin (agonists, genetics, metabolism)
• GTPase-Activating Proteins (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Injections, Intraperitoneal
• Macrophages (drug effects, metabolism, pathology)
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Necrosis (chemically induced, genetics, pathology, prevention & control)
• Pancreatic Elastase (administration & dosage)
• Protein-Lysine 6-Oxidase (genetics, metabolism)
• Tropoelastin (agonists, genetics, metabolism)