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.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Aortic Aneurysm, Abdominal/drug therapy , Cardiovascular Agents/pharmacology , GTPase-Activating Proteins/antagonists & inhibitors , Imidazoles/pharmacology , Indoles/pharmacology , Necrosis/prevention & control , Animals , Aortic Aneurysm, Abdominal/chemically induced , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/pathology , Apoptosis/drug effects , Cell Movement/drug effects , Disease Models, Animal , Elastin/agonists , Elastin/genetics , Elastin/metabolism , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Gene Expression Regulation , Humans , Injections, Intraperitoneal , Macrophages/drug effects , Macrophages/metabolism , Macrophages/pathology , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Necrosis/chemically induced , Necrosis/genetics , Necrosis/pathology , Pancreatic Elastase/administration & dosage , Protein-Lysine 6-Oxidase/genetics , Protein-Lysine 6-Oxidase/metabolism , Tropoelastin/agonists , Tropoelastin/genetics , Tropoelastin/metabolismABSTRACT
PURPOSE: To determine the effect of age on the biomechanical properties of the intralamellar matrix of single annulus fibrosus (AF) lamellae. METHODS: One intervertebral disc (IVD) was excised from five young (<12 months), five middle-aged (2-4 years) and five older (5-7 years) ovine lumbar spines. From each IVD, a maximum of four single AF lamellae samples were harvested: two from the anterior region and two from the posterior region. Tissues were mounted in a tensile testing apparatus such that tension was applied perpendicular to the orientation of the collagen fibers to isolate the intralamellar matrix. Variables of interest from the stress-strain relationship were: end of toe-region strain and corresponding stress, initial failure stress and strain, and elastic stiffness. RESULTS: When compared to the middle-aged and old samples, the intralamellar matrix of young AF samples displayed significantly higher stress values at the end of the end of toe-region (p = 0.008) and at initial failure (p = 0.002). Further, the young samples were stiffer than both middle-aged and old samples (p = 0.04). CONCLUSIONS: This study was the first to show that the intralamellar matrix of single AF lamellae is weaker and more compliant in middle-aged and old ovine IVDs compared to young IVDs. These findings are likely a result of the remarkable age-related changes that occur that ultimately weaken the IVD as a whole.
Subject(s)
Aging/physiology , Annulus Fibrosus/physiology , Lumbar Vertebrae/physiology , Animals , Biomechanical Phenomena/physiology , Sheep , Stress, Mechanical , Tensile Strength/physiologyABSTRACT
The current study examined of the effect of intermittent, short-term periods of full trunk flexion on the development of low back pain (LBP) during two hours of standing. Sixteen participants completed two 2-h standing protocols, separated by one week. On one day, participants stood statically for 2h (control day); on the other day participants bent forward to full spine flexion (termed flexion trials) to elicit the flexion relaxation (FR) phenomenon for 5s every 15min (experimental day). The order of the control and experimental day was randomized. During both protocols, participants reported LBP using a 100mm visual analogue scale every 15min. During the flexion trials, lumbar spine posture, erector spinae and gluteus medius muscle activation was monitored. Ultimately, intermittent trunk flexion reduced LBP by 36% (10mm) at the end of a 2-h period of standing. Further, erector spinae and gluteus medius muscle quietening during FR was observed in 91% and 65% of the flexion trials respectively, indicating that periods of rest did occurred possibly contributing to the reduction in LBP observed. Since flexion periods do not require any aids, they can be performed in most workplaces thereby increasing applicability.
