Matricellular protein CCN3 mitigates abdominal aortic aneurysm

C. Zhang, D. Van Der Voort, H. Shi, R. Zhang, Y. Qing, S. Hiraoka, M. Takemoto, K. Yokote, J.V. Moxon, Paul Norman, L. Rittié, H. Kuivaniemi, G.B. Atkins, S.L. Gerson, G.P. Shi, J. Golledge, N. Dong, B. Perbal, D.A. Prosdocimo, Z. Lin

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1282-1299
JournalJournal of Clinical Investigation
Volume126
Issue number4
DOIs
Publication statusPublished - 2016

Fingerprint Dive into the research topics of 'Matricellular protein CCN3 mitigates abdominal aortic aneurysm'. Together they form a unique fingerprint.

  • Cite this

    Zhang, C., Van Der Voort, D., Shi, H., Zhang, R., Qing, Y., Hiraoka, S., Takemoto, M., Yokote, K., Moxon, J. V., Norman, P., Rittié, L., Kuivaniemi, H., Atkins, G. B., Gerson, S. L., Shi, G. P., Golledge, J., Dong, N., Perbal, B., Prosdocimo, D. A., & Lin, Z. (2016). Matricellular protein CCN3 mitigates abdominal aortic aneurysm. Journal of Clinical Investigation, 126(4), 1282-1299. https://doi.org/10.1172/JCI82337