From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA.
Hypertension. 2018 Oct;72(4):909-917. doi: 10.1161/HYPERTENSIONAHA.118.11666.
SDF-1α (stromal cell-derived factor-1α) is a CXCR4-receptor agonist and DPP4 (dipeptidyl peptidase 4) substrate. SDF-1α, particularly when combined with sitagliptin to block the metabolism of SDF-1α by DPP4, stimulates proliferation of cardiac fibroblasts via the CXCR4 receptor; this effect is greater in cells from spontaneously hypertensive rats versus Wistar-Kyoto normotensive rats. Emerging evidence indicates that ubiquitin(1-76) exists in plasma and is a potent CXCR4-receptor agonist. Therefore, we hypothesized that ubiquitin(1-76), similar to SDF-1α, should increase proliferation of cardiac fibroblasts. Contrary to our working hypothesis, ubiquitin(1-76) did not stimulate cardiac fibroblast proliferation, yet unexpectedly antagonized the proproliferative effects of SDF-1α combined with sitagliptin. In this regard, ubiquitin(1-76) was more potent in spontaneously hypertensive versus Wistar-Kyoto cells. In the presence of 6bk (selective inhibitor of insulin-degrading enzyme [IDE]; an enzyme known to convert ubiquitin(1-76) to ubiquitin(1-74)), ubiquitin(1-76) no longer antagonized the proproliferative effects of SDF-1α/sitagliptin. Ubiquitin(1-74) also antagonized the proproliferative effects of SDF-1α/sitagliptin, and this effect of ubiquitin(1-74) was not blocked by 6bk and was >10-fold more potent compared with ubiquitin(1-76). Neither ubiquitin(1-76) nor ubiquitin(1-74) inhibited the proproliferative effects of the non-CXCR4 receptor agonist neuropeptide Y (activates Y receptors). Cardiac fibroblasts expressed IDE mRNA, protein, and activity and converted ubiquitin(1-76) to ubiquitin(1-74). Spontaneously hypertensive fibroblasts expressed greater IDE activity. Extracellular ubiquitin(1-76) blocks the proproliferative effects of SDF-1α/sitagliptin via its conversion by IDE to ubiquitin(1-74), a potent CXCR4 antagonist. Thus, IDE inhibitors, particularly when combined with DPP4 inhibitors or hypertension, could increase the risk of cardiac fibrosis.
基质细胞衍生因子 1α（stromal cell-derived factor-1α）是趋化因子受体 4 的激动剂和二肽基肽酶 4（dipeptidyl peptidase 4）的底物。SDF-1α，特别是与西他列汀联合使用以阻止 DPP4 对 SDF-1α 的代谢，通过 CXCR4 受体刺激心脏成纤维细胞的增殖；这种作用在自发性高血压大鼠的细胞中比 Wistar-Kyoto 正常血压大鼠的细胞中更大。新出现的证据表明，泛素（1-76）存在于血浆中，是一种有效的 CXCR4 受体激动剂。因此，我们假设泛素（1-76）与 SDF-1α 相似，应该增加心脏成纤维细胞的增殖。与我们的工作假设相反，泛素（1-76）并未刺激心脏成纤维细胞的增殖，但出人意料地拮抗了 SDF-1α 与西他列汀联合使用的促增殖作用。在这方面，泛素（1-76）在自发性高血压大鼠中的作用比 Wistar-Kyoto 细胞更强。在 6bk（胰岛素降解酶[IDE]的选择性抑制剂的存在下；已知将泛素（1-76）转化为泛素（1-74）的酶），泛素（1-76）不再拮抗 SDF-1α/西他列汀的促增殖作用。泛素（1-74）也拮抗了 SDF-1α/西他列汀的促增殖作用，并且这种作用不受 6bk 阻断，并且比泛素（1-76）强 10 倍以上。泛素（1-76）和泛素（1-74）都不抑制非 CXCR4 受体激动剂神经肽 Y（激活 Y 受体）的促增殖作用。心脏成纤维细胞表达 IDE mRNA、蛋白和活性，并将泛素（1-76）转化为泛素（1-74）。自发性高血压成纤维细胞表达更高的 IDE 活性。细胞外泛素（1-76）通过其被 IDE 转化为泛素（1-74）来阻断 SDF-1α/西他列汀的促增殖作用，泛素（1-74）是一种有效的 CXCR4 拮抗剂。因此，IDE 抑制剂，特别是与 DPP4 抑制剂或高血压联合使用时，可能会增加心脏纤维化的风险。
