elastin and beta-aminopropionitrile-fumarate

Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.

Topics: Aminopropionitrile; Angiotensin II; Animals; Aortic Dissection; Disease Models, Animal; Elastin; Humans; Inflammation; Matrix Metalloproteinase 8; Mice; Mice, Knockout; Reactive Oxygen Species; Vascular Cell Adhesion Molecule-1

Abdominal aortic aneurysm (AAA) is a significant medical problem with a high mortality rate. Nevertheless, the underlying mechanism for the progression and regression of AAA is unknown.. Experimental model of AAA was first created by porcine pancreatic elastase incubation around the infrarenal aorta of C57BL/6 mice. Then, AAA progression and regression were evaluated based on the diameter and volume of AAA. The aortas were harvested for hematoxylin-eosin staining (HE), orcein staining, sirius red staining, immunofluorescence analysis and perls' prussian blue staining at the indicated time point. Finally, β-aminopropionitrile monofumarate (BAPN) was used to explore the underlying mechanism of the regression of AAA.. When we extended the observation period to 100 days, we not only observed an increase in the AAA diameter and volume in the early stage, but also a decrease in the late stage. Consistent with AAA diameter and volume, the aortic thickness showed the same tendency based on HE staining. The elastin and collagen content first degraded and then regenerated, which corresponds to the early deterioration and late regression of AAA. Then, endogenous up-regulation of lysyl oxidase (LOX) was detected, accompanying the regression of AAA, as detected by an immunofluorescent assay. BAPN and LOX inhibitor considerably inhibited the regression of AAA, paralleling the degradation of elastin lamella and collagen.. Taken together, we tentatively conclude that endogenous re-generation of LOX played an influential role in the regression of AAA. Therefore, regulatory factors on the generation of LOX exhibit promising therapeutic potential against AAA.

Topics: Aminopropionitrile; Animals; Aortic Aneurysm, Abdominal; Collagen; Disease Models, Animal; Disease Progression; Elastin; Extracellular Matrix Proteins; Mice; Mice, Inbred C57BL; Pancreatic Elastase; Protein-Lysine 6-Oxidase; Up-Regulation

Topics: Amino Acids; Aminopropionitrile; Animals; Chemical Phenomena; Chemistry; Collagen; Elastin; Hydrazines; Lathyrism; Male; Oxalates; Penicillamine; Pyridinium Compounds; Rats; Rats, Inbred Strains; Semicarbazides