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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- κ B) pathway, regulates the paracrine effects of MSC-mediated heart repair following infarction. NF- κ B activity of stromal cells was increased by Rap1 as measured by pNF- κ B-luciferase reporter activity, and this was abolished by IkB-dominant-negative protein. Knockdown of Rap1 with shRap1 resulted in diminished translocation of p65-NF- κ B 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- κ B to NF- κ B-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- κ B 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- κ B 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.

Rap1-mediated nuclear factor-kappaB (NF-κB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction