Bone marrow derived stromal cells modified by adenovirus-mediated HIF-1alpha double mutant protect cardiac myocytes against CoCl2-induced apoptosis

• Published in: Toxicology in vitro Vol. 23; no. 6; p. 1069
• Main Authors: Wang, Yesong, Sun, Aijiao, Xue, Jiaojie, Feng, Chong, Li, Jun, Wu, Juekan
• Format: Journal Article
• Language: English
• Published: England 01.09.2009
• Subjects: Adenoviridae - genetics; Animals; Apoptosis - drug effects; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cells, Cultured; Cobalt - toxicity; Coculture Techniques; Gene Expression Regulation; Genetic Vectors; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mutation; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Stromal Cells - drug effects; Stromal Cells - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1879-3177
• DOI: 10.1016/j.tiv.2009.06.002

Bone marrow derived stromal cells (MSCs) can prevent the apoptosis of ischemic cardiomyocytes (CMCs). This anti-apoptosis activity may be related to an activation of the HIF-1alpha signal pathway in MSCs. Therefore, we investigated protective effects of an adenovirus (Ad)-mediated active form of HIF-1alpha (HIF-1alpha-Ala564-Ala803) modified MSCs on CMCs against CoCl(2)-induced apoptosis. At normoxia, pAd-HIF1alpha-Ala564-Ala803 exhibited a stable HIF-1alpha protein expression in MSCs. Compared with the single CMC culture, the TGF-beta1 level and the Bcl-2 expression were significantly increased, concomitant with a reduced expression of caspase-3, the LDH release and TUNEL-positive CMCs in CMC and MSC, beta-galactosidase (LacZ)-MSC or HIF-1alpha-Ala564-Ala803-MSC coculture exposed to CoCl(2). Furthermore, these effects were more prominent in CMC and HIF-1alpha-Ala564-Ala803-MSC coculture than in CMC and MSC or LacZ-MSC coculture exposed to CoCl(2). Pre-transfection of TGF-beta1-small interfering RNA (siRNA) effectively inhibited the TGF-beta1 level, resulting in a dramatic reduction in the Bcl-2 expression as well as an increased level of apoptosis in CMC and HIF-1alpha-Ala564-Ala803-MSC coculture exposure to CoCl(2), whereas pre-transfection of green fluorescent protein (GFP)-siRNA had no such effects. These data suggest that HIF1alpha-Ala564-Ala803 modified MSCs have better protective effects of CMCs against the CoCl(2)-induced apoptosis and these protective effects are at least partly TGF-beta1-mediated.