TY - JOUR
T1 - Matricellular protein CCN3 mitigates abdominal aortic aneurysm
AU - Zhang, Chao
AU - Van Der Voort, Dustin
AU - Shi, Hong
AU - Zhang, Rongli
AU - Qing, Yulan
AU - Hiraoka, Shuichi
AU - Takemoto, Minoru
AU - Yokote, Koutaro
AU - Moxon, Joseph V.
AU - Norman, Paul
AU - Rittié, Laure
AU - Kuivaniemi, Helena
AU - Atkins, G. Brandon
AU - Gerson, Stanton L.
AU - Shi, Guo Ping
AU - Golledge, Jonathan
AU - Dong, Nianguo
AU - Perbal, Bernard
AU - Prosdocimo, Domenick A.
AU - Lin, Zhiyong
N1 - Funding Information:
This work was supported by NIH grants HL117759 and AA021390 (to Z. Lin). This work was also supported in part by the National Nature Science Foundation of China (grant number 31330029).
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI82337
DO - 10.1172/JCI82337
M3 - Article
C2 - 26974158
AN - SCOPUS:84964589716
SN - 0021-9738
VL - 126
SP - 1282
EP - 1299
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -