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Matricellular protein CCN3 mitigates abdominal aortic aneurysm
Chao Zhang, … , Domenick A. Prosdocimo, Zhiyong Lin
Chao Zhang, … , Domenick A. Prosdocimo, Zhiyong Lin
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1282-1299. https://doi.org/10.1172/JCI82337.
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Research Article Vascular biology

Matricellular protein CCN3 mitigates abdominal aortic aneurysm

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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

Chao Zhang, Dustin van der Voort, Hong Shi, Rongli Zhang, Yulan Qing, Shuichi Hiraoka, Minoru Takemoto, Koutaro Yokote, Joseph V. Moxon, Paul Norman, Laure Rittié, Helena Kuivaniemi, G. Brandon Atkins, Stanton L. Gerson, Guo-Ping Shi, Jonathan Golledge, Nianguo Dong, Bernard Perbal, Domenick A. Prosdocimo, Zhiyong Lin

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Figure 1

CCN3 expression is reduced in AAA.

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CCN3 expression is reduced in AAA.
(A) Western blot of CCN3 protein in m...
(A) Western blot of CCN3 protein in mouse abdominal aorta tissue from Apoe-null mice infused with saline or Ang II for 4 weeks. n = 5–6. (B) CCN3 mRNA expression from human abdominal aorta tissue without and with AAA, n = 5–6 per group, Mann-Whitney U test. Representative image of CCN3 protein expression by immunofluorescence staining (C) and quantification from control human nonaneurysmal infrarenal aorta and AAA (D). Scale bars: 50 μm. Red, SMA; green, CCN3; orange, overlay of SMA (red) and CCN3 (green). Mann-Whitney U test.
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