Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07103, USA.
Center for Advanced Proteomics Research, Department of Biochemistry & Molecular Biology, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.
Nat Commun. 2023 Sep 19;14(1):5805. doi: 10.1038/s41467-023-41595-x.
The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway.
Bcl-xL 在缺血/再灌注期间的心脏中的抗凋亡功能通过 K-Ras-Mst1 介导的 Ser14 磷酸化减弱，这允许 Bcl-xL 从 Bax 解离，并促进心肌细胞死亡。在这里，我们表明，Bcl-xL 的 Ser14 磷酸化也通过心脏中的血液动力学应激，通过 H-Ras-ERK 途径促进。Bcl-xL Ser14 磷酸化抗性敲入雄性小鼠在急性压力超负荷期间发展出较少的心肌肥厚，并表现出收缩功能障碍和死亡率增加。Bcl-xL Ser14 磷酸化通过阻断 Bcl-xL 和 IP3R 之间的抑制相互作用增强 Ca2+ 瞬变，从而促进 Ca2+ 释放和钙调神经磷酸酶-NFAT 途径的激活，这是一种促进心肌肥厚的 Ca2+ 依赖性机制。这些结果表明，急性压力超负荷时 Bcl-xL 在 Ser14 处的磷酸化在通过诱导 Bcl-xL 从 IP3R 释放从而介导代偿性肥厚方面发挥重要作用，减轻了 Bcl-xL 对 IP3R-NFAT 途径的负约束。
