Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling

Abstract

Aims Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation 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 telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ 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 TGFβ signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes. Conclusion Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ 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.

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

“…Previous reports indicated that the phosphorylated SMAD3 is elevated markedly in the lung of G3 TERC –/– mice ( Liu et al, 2018 ), and SMAD3 binds directly to the promoter of TERT gene and induces TERT gene repression ( Li and Liu, 2007 ; Cassar et al, 2010 ). By inhibiting phosphorylation of SMAD2/3, which prevents repression of TERT, Pim1 maintains telomere lengths in cardiomyocytes ( Ebeid et al, 2021 ). Our results indicate that GDF11 maintains telomere length in Neuro 2a cells, unlike TGF-β which shortens telomere in cancer cells ( Li and Liu, 2007 ; Cassar et al, 2010 ).…”

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

“…Decades of cardioprotective signal transduction studies have produced an intricate web of relationships between mediators of cardiomyocyte survival. Our group were pioneers in establishing PIM1-mediated cardioprotection in over a decade of studies [ 8 , 9 , 16 , 29 , 30 , 33 , 34 , 35 ], which was subsequently reinforced by studies from other researchers [ 7 , 10 , 36 , 37 ]. Similarly, cardioprotection is also conferred by c-Kit activity [ 17 , 32 , 38 ], with c-Kit biology inextricably linked to myocardial homeostasis [ 39 , 40 ].…”

“…In summary, PIM1 upregulates c-Kit protein expression to promote protection in cardiomyocytes, consistent with cumulative evidence of cardioprotection as well as preservation of a more “youthful” phenotype mediated by PIM1 overexpression [ 9 , 29 , 34 , 53 ]. Reinforcement of c-Kit activity by PIM1 could account for the ability of PIM1 to antagonize cellular senescence [ 33 , 53 ] and serve as the basis for future studies. Mechanistic understanding of PIM1-mediated cardioprotection could provide valuable information towards the protection of cardiomyocytes to promote cardiac repair.…”

Cellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease

“…CMs belong to postmitotic cells, and biomechanical stress, oxidative stress, and inflammation can also cause telomere attrition, eventually leading to cellular senescence [ 123 , 124 ]. Hyperglycemia accelerates senescence in CMs by inducing various cellular stressors, such as oxidative stress, DNA damage, and telomere erosion, which is a well-accepted reason for the increased incidence of cardiovascular disease in diabetic individuals [ 118 ].…”

“…Heme oxygenase-1 (HO-1) plays a role in reducing cellular senescence in the process of MI and cardiac aging [ 125 ]. Ebeid DE et al found that PIM1 is a myocardial protective kinase that delays cellular senescence by maintaining the telomere length [ 123 ]. Rb1 and Meis homeobox 2 (Meis2) is a set of cell cycle inhibitors [ 126 ].…”