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Vascular Smooth Muscle Cell Apoptosis Promotes Transplant Arteriosclerosis Through Inducing the Production of SDF‐1α
Author(s) -
Li J.,
Liu S.,
Li W.,
Hu S.,
Xiong J.,
Shu X.,
Hu Q.,
Zheng Q.,
Song Z.
Publication year - 2012
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2012.04082.x
Subject(s) - arteriosclerosis , medicine , apoptosis , transplantation , mesenchymal stem cell , cancer research , pi3k/akt/mtor pathway , microbiology and biotechnology , immunology , pathology , biology , signal transduction , biochemistry
Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild‐type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF‐1α from apoptotic and neighboring viable cells, resulting in increased SDF‐1α in the culture media. Conditioned media from Ltv‐p53‐transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF‐1α‐dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus‐mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF‐1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90 + CD105 + double‐positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF‐1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions.