title: Matricellular protein CCN3 mitigates abdominal aortic aneurysm.
abstract: Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II-induced AAA and elastase perfusion-stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II-induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Dustin
authors.initials: D
authors.lastname: van der Voort
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qing
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Minoru
authors.initials: M
authors.lastname: Takemoto
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Moxon
authors.forename: Paul
authors.initials: P
authors.lastname: Norman
authors.forename: Laure
authors.initials: L
authors.lastname: Rittié
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.forename: G Brandon
authors.initials: GB
authors.lastname: Atkins
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
authors.forename: Nianguo
authors.initials: N
authors.lastname: Dong
authors.forename: Bernard
authors.initials: B
authors.lastname: Perbal
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D055514:Nephroblastoma Overexpressed Protein / Q000235:genetics / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000633:toxicity
chemical_list: C526320:Ccn3 protein, mouse; D055514:Nephroblastoma Overexpressed Protein; D000804:Angiotensin II; D004549:Elastin; D010196:Pancreatic Elastase