Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling
Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling
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DOI：
10.1093/cvr/cvaa066
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发表时间：
2021-01-01
影响因子：
10.8
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
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作者：
Ebeid, David E.;Khalafalla, Farid G.;Sussman, Mark A.
目的心肌细胞端粒磨损与收缩力下降、细胞衰老和促凋亡转录因子上调有关。Pim1是一种心脏保护激酶，通过维持端粒长度来对抗心肌细胞的衰老表型并延缓细胞衰老，但其机制尚不清楚。另一个负责调节端粒长度的途径是转化生长因子β (TGF β)信号通路，抑制TGF β信号传导维持端粒长度。Pim1与TGF β之间的关系尚未探讨。本研究通过Pim1与TGF β信号通路组分在A549细胞增殖和有丝分裂后心肌细胞中的相互作用，揭示了端粒长度调控的机制。方法和结果在re A549细胞中，通过慢病毒介导的过表达PIM1和抑制TGF β信号传导来维持端粒长度。通过对TGF - β信号的药理抑制，在小鼠的心肌细胞中进一步证实了端粒长度的维持，这些心肌细胞具有心肌特异性的PIM1过表达。机制上，Pim1抑制Smad2的磷酸化，阻止Smad2易位进入细胞核，抑制TGF β通路基因的表达。结论Pim1通过抑制TGF β通路下游效应物Smad2和Smad3的磷酸化来维持心肌细胞端粒长度，从而阻止端粒酶逆转录酶的抑制。这项研究的发现证明了端粒长度维持的一种新机制，并为保持心脏功能提供了潜在的靶点。
Aims Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and upregulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating tetomere length is the transforming growth factor beta (TGF beta) signalling pathway where inhibiting TGF beta signalling maintains telomere Length. The relationship between Pim1 and TGF beta has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGF beta signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.Methods and results Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGF beta signalling in re A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGF beta signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGF beta pathway genes.Conclusion Pim1 maintains tetomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGF beta pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.[GRAPHICS].