Young patients with psoriasis have increased arterial stiffness but not microvascular dysfunction compared with healthy controls. More importantly, hs-CRP positively correlated with, and independently predicted, arterial stiffness. This suggests that systemic inflammation in patients with psoriasis is associated with premature atherosclerosis.
Paracrine effect is the major mechanism that underlies mesenchymal stem cells (MSC)-based therapy. This study aimed to examine how Rap1, telomeric repeat-binding factor 2-interacting protein 1 (Terf2IP), which is a novel modulator involved in the nuclear factor-kappaB (NF-κB) pathway, regulates the paracrine effects of MSC-mediated heart repair following infarction. NF-κB activity of stromal cells was increased by Rap1 as measured by pNF-κB-luciferase reporter activity, and this was abolished by IkB-dominant-negative protein. Knockdown of Rap1 with shRap1 resulted in diminished translocation of p65-NF-κB from the cytoplasm to nuclei in response to tumor necrosis factor-α (TNF-α) stimulation. Compared with BM-MSCs, Rap1−/−-BM-MSCs displayed a significantly reduced ratio of phosphorylated NF-κB to NF-κB-p65 and of Bax to Bcl-2, and increased resistance to hypoxia-induced apoptosis by the terminal deoxynucleotidal transferase-mediated dUTP nick end labeling (TUNEL) assay. In contrast, re-expression of Rap1 in Rap1−/−-BM-MSCs resulted in loss of resistance to apoptosis in the presence of hypoxia. Moreover, absence of Rap1 in BM-MSCs led to downregulation of NF-κB activity accompanied by reduced pro-inflammatory paracrine cytokines TNF-α, IL (interleukin)-6 and monocyte chemotactic protein-1 in Rap1−/−-BM-MSCs compared with BM-MSCs. The apoptosis of neonatal cardiomyocytes (NCMCs) induced by hypoxia was significantly reduced when cocultured with Rap1−/−-BM-MSC hypoxic-conditioned medium (CdM). The increased cardioprotective effects of Rap1−/−-BM-MSCs were reduced when Rap1−/−-BM-MSCs were reconstituted with Rap1 re-expression. Furthermore, in vivo study showed that transplantation of Rap1−/−-BM-MSCs significantly improved heart function, decreased infarct size, prevented cardiomyocyte apoptosis and inhibited inflammation compared with controls and BM-MSCs (P<0.01). This study reveals that Rap1 has a critical role in the regulation of MSC paracrine actions. Compared with BM-MSCs, Rap1−/−-BM-MSCs decreased NF-κB sensitivity to stress-induced pro-inflammatory cytokine production and reduced apoptosis. Selective inhibition of Rap1 in BM-MSCs may be a novel strategy to enhance MSC-based therapeutic efficacy in myocardial infarction.
Recent studies suggest that reductions in circulating endothelial progenitor cells (EPCs) may contribute to the development of atherosclerosis. However, whether reduced circulating EPCs contribute to cerebrovascular disease remains undefined. We tested the hypothesis that reduced circulating EPCs was associated with an increased burden of carotid atherosclerosis. The level of circulating CD34 þ /KDR þ EPCs and the extent of carotid atherosclerosis were determined in 30 patients with a history of atherothrombotic ischaemic stroke and 30 age-and sex-matched controls (mean age: 6372 years; 63% men). Stroke patients, compared with controls, had significantly higher carotid mean maximum intima-media thickness (mmIMT) (1.0870.05 versus 0.9070.02 mm, P ¼ 0.002), prevalence of carotid plaque (60.0 versus 23.3%, P ¼ 0.004) and a lower number of circulating CD34 þ /KDR þ EPCs (235.7745.5 versus 400.4756.8 cells/ll, P ¼ 0.027). The circulating CD34 þ /KDR þ EPC count correlated negatively with carotid mmIMT (r ¼ À0.50, Po0.001), and was an independent risk factor for increased carotid mmIMT41 mm (odds ratio (OR): 7.71; 95% confidence interval (CI): 1.62-36.74, P ¼ 0.010) and the presence of carotid plaque (OR: 7.04; 95% CI: 1.95-25.43, P ¼ 0.003). Furthermore, stroke patients with low (o25th percentile of controls) as compared to those with normal CD34 þ /KDR þ EPC count had a significantly greater carotid mmIMT (1.217 0.07 versus 0.9370.05 mm, P ¼ 0.005) and a significantly higher prevalence of carotid plaque (87.5% versus 28.6%; P ¼ 0.001). Our observations suggested that reduced circulating EPC may contribute to the progression of carotid atherosclerosis. Circulating EPC count may provide a novel marker for the burden of carotid atherosclerosis.
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