Mechanism Of Extracellular Matrix Protein CCN3 Limiting Development And Progression Of Abdominal Aortic Aneurysm

Part ?. CCN3 Plays a Protective Role on Progression of Abdominal Aortic AneurysmObject:CCN3 expression reduced in human and rodent abdominal aortic aneurysm tissue.Methods:Administered with Ang?-releasing controlled pump percutaneous insertion or transient perfused with elastase in abdominal aortic artery, Ccn3-/-mice prone to develop AAA compared with WT mice.Results:Pathological features of mice abdominal aortic artery recapitulated that of human AAA:inflammatory cell infiltration, matrix metalloproteinase activity up-regulation, vascular smooth muscle cell apoptosis and heightened reactive oxygen species (ROS). Conversely, lentiviral mediated overexpression of CCN3 mitigates elastase-mediate AAA progression in mice.Discussion:CCN3 plays a protective role on progression of AAA.Part II. Mechanism research of ERK Pathway and ROS Function in Treatment Induced Abdominal Aortic Aneurysm on CCN3 Deficient miceObject:In order to find out the essential cell in induced AAA on CCN3 deficient mice, we carried on bilateral bone marrow transplantation experiments.Methods and Results:With Angiotensin II induced, no matter bone marrow cells expressing CCN3 or not, vascular intrinsic CCN3 deficient mice developed AAA, which indicated vascular cells played major role in CCN3-deficiency AAA model. Based on the highest CCN3 expression among vascular cells and well-known important role in AAA, primary mouse aortic smooth muscle cells were cultured in vitro. After stimulation CCN3 deficient SMC group had more cell apoptosis, inflammatory cytokines expression and ROS production, ERK1/2 phosphorylation, which recapitulated in CCN3-Knockout AAA tissue. Genetic knocking out ERK1 or pharmacological inhibiting ERK1/2 phosphorylation limited the progression of Ang? induced AAA in CCN3 deficient mice. We got similar inhibition effect with ROS production blocking.Discussion:Based on these results, we confer the ERK1/2 pathway and ROS production serves as an important role in the regulation of CCN3-dependent AAA development, CCN3 as an essential player in regulating vascular inflammation.