Abstract:The dysfunction of endothelial progenitor cells (EPCs) was found to be associated with vascular complications in diabetes mellitus (DM) patients. Previous studies found that regular exercise could improve the function of EPCs in DM patients, but the underling mechanism was unclear. Irisin, a newly identified myokine, was induced by exercise and has been demonstrated to mediate some of the positive effects of exercise. In this study, we hypothesize that irisin may have direct effects on EPC function in DM mice. These data showed for the first time that irisin increased the number of EPCs in peripheral blood of DM mice and improved the function of EPCs derived from DM mice bone marrow. The mechanism for the effect of irisin is related to the PI3K/Akt/eNOS pathway. Furthermore, irisin was demonstrated to improve endothelial repair in DM mice that received EPC transplants after carotid artery injury. The results of this study indicate a novel effect of irisin in regulating the number and function of EPCs via the PI3K/Akt/eNOS pathway, suggesting a potential for the administration of exogenous irisin as a succedaneum to improve EPC function in diabetic patients who fail to achieve such improvements through regular exercise.

Connexins 43 (Cx43) plays a key role in neointimal formation after vascular injury, but the mechanism still needs to be further explored. We hypothesized that the gap junction-dependent function of Cx43 to mediate intercellular communication has a crucial role in the development and progression of vascular diseases. The effect of intercellular communication mediated by Cx43 hemichannels on neointimal formation after vascular injury was investigated. Cx43 was overexpressed or knockdown in rat vascular smooth muscle cell (SMC) by transfection pcDNA-Cx43 plasmid or small interfering RNA (siRNA) against Cx43 (siCx43). SMC proliferation and marker genes expression after Cx43 alteration and blockade of the Cx43 hemichannel were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and RT-PCR. The effect of carbenoxolone on neointimal formation was investigated in carotid artery injured rat model. We demonstrated that overexpression of Cx43 promoted SMC proliferation, meanwhile, mRNA expression level of smooth muscle alpha-actin and calponin, which were important markers of SMC in a contractile state, were down-regulated in smooth muscle. Knockdown of Cx43 inhibited SMC proliferation but increased SMC marker genes expression level. Carbenoxolone (50 muM) improved SMC contractile differentiation and inhibited its proliferation. Our data showed that carbenoxolone reduced neointimal formation after carotid artery injury. In summary, blockade of intercellular communication via Cx43 hemichannels reduces neointimal formation after vascular injury by inhibiting proliferation and phenotypic modulation of SMCs.

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Risk factors for coronary heart disease including low-density lipoprotein (LDL) cholesterol can reduce the number and activity of endothelial progenitor cells (EPCs), thereby hindering their usefulness for treating cardiovascular disease in transplants. The aim of this study was to investigate whether hepatocyte growth factor (HGF) can protect EPCs from the inhibition caused by LDL cholesterol. EPCs derived from mouse bone marrow were isolated and cultured in medium supplemented with different concentrations of LDL cholesterol. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, modified Boyden chambers and flow cytometry were used to evaluate EPC proliferation, migration and apoptosis. The role of Akt in this process was also evaluated through observing the expressions of total Akt and Akt phosphorylation, and pharmacological analysis. Our results indicate that LDL cholesterol inhibits the proliferation and migration of EPCs, and induces their apoptosis. However, HGF improves the activity of EPCs inhibited by LDL cholesterol, and it simultaneously decreases EPC apoptosis induced by LDL cholesterol. Blockade of phosphoinositide-3 kinase (PI3K) by Ly294002 attenuates the effect of HGF. Furthermore, our experiments suggest that HGF increases the level of phosphorylated Akt in EPCs rather than Akt. However, PI3K inhibitor reduces the increase of phosphorylated Akt level induced by HGF. These findings suggest HGF promotes endothelial progenitor cells migration, proliferation and survival impaired by low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway.

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IntroductionRenal interstitial fibrosis (RIF) is a significant cause of end-stage renal failure. The goal of this study was to characterize the distribution of transplanted induced autologous stem cells in a rabbit model of renal interstitial fibrosis and evaluate its therapeutic efficacy for treatment of renal interstitial fibrosis.MethodsA rabbit model of renal interstitial fibrosis was established. Autologous fibroblasts were cultured, induced and labeled with green fluorescent protein (GFP). These labeled stem cells were transplanted into the renal artery of model animals at 8 weeks.ResultsEight weeks following transplantation of induced autologous stem cells, significant reductions (P < 0.05) were observed in serum creatinine (SCr) (14.8 ± 1.9 mmol/L to 10.1 ± 2.1 mmol/L) and blood urea nitrogen (BUN) (119 ± 22 µmol/L to 97 ± 13 µmol/L), indicating improvement in renal function.ConclusionsWe successfully established a rabbit model of renal interstitial fibrosis and demonstrated that transplantation of induced autologous stem cells can repair kidney damage within 8 weeks. The repair occurred by both inhibition of further development of renal interstitial fibrosis and partial reversal of pre-existing renal interstitial fibrosis. These beneficial effects lead to the development of normal tissue structure and improved renal function.