Division of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Cell Mol Med. 2024 Sep;28(17):e70069. doi: 10.1111/jcmm.70069.
Phosphoinositide 3-kinase γ (PI3Kγ) is G-protein-coupled receptor-activated lipid kinase with both kinase-dependent and kinase-independent activity. Plenty of evidence have demonstrated that PI3Kγ participated in TAC and I/R-induced myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in the PI3Kγ gene (PIK3CG) were associated with the prognosis of HF in the Chinese Han population. Through re-sequencing and genotyping, we finally identified a common variant in the 3'UTR of PIK3CG strongly associated with the prognosis of HF in two-stage population: adjusted p = 0.007, hazard ratio = 0.56 (0.36-0.85) in the first cohort and adjusted p = 0.024, hazard ratio = 0.39 (0.17-0.88) in the replicated cohort. A series of functional assays revealed that rs10215499-A allele suppressed PIK3CG translation by facilitating has-miR-133a-3p binding, but not the G allele. Subjects carrying the GG genotype showed higher mRNA and protein level than those with AA and AG genotype. Furthermore, overexpression of PIK3CG could protect AC16 from hypoxia/reoxygenation (H/R)-induced apoptosis, while the case was opposite for PIK3CG silencing. In conclusion, common variant rs10215499 in the 3'-UTR of PIK3CG might affect the prognosis of HF by interfering with miR-133a-3p binding and PIK3CG is a promising target for HF treatment in the future.
磷酸肌醇 3-激酶 γ（PI3Kγ）是一种 G 蛋白偶联受体激活的脂质激酶，具有激酶依赖性和激酶非依赖性活性。大量证据表明，PI3Kγ 参与了 TAC 和 I/R 诱导的心肌重构和心力衰竭（HF）。在这项研究中，我们检验了这样一个假设，即在 PI3Kγ 基因（PIK3CG）中的常见变异与中国汉族人群 HF 的预后有关。通过重新测序和基因分型，我们最终确定了 PIK3CG 的 3'UTR 中的一个常见变异与两阶段人群 HF 的预后密切相关：在第一队列中，调整后的 p 值为 0.007，危险比为 0.56（0.36-0.85），在复制队列中，调整后的 p 值为 0.024，危险比为 0.39（0.17-0.88）。一系列功能测定表明，rs10215499-A 等位基因通过促进 has-miR-133a-3p 结合而抑制 PIK3CG 翻译，但 G 等位基因则没有。携带 GG 基因型的个体的 mRNA 和蛋白水平高于 AA 和 AG 基因型的个体。此外，PIK3CG 的过表达可以保护 AC16 免受缺氧/复氧（H/R）诱导的凋亡，而 PIK3CG 沉默则相反。总之，PIK3CG 3'-UTR 中的常见变异 rs10215499 可能通过干扰 miR-133a-3p 结合而影响 HF 的预后，并且 PIK3CG 可能成为未来 HF 治疗的一个有前途的靶点。
