Format

Send to

Choose Destination
Cardiovasc Res. 2020 Mar 16. pii: cvaa066. doi: 10.1093/cvr/cvaa066. [Epub ahead of print]

Pim1 Maintains Telomere Length in Mouse Cardiomyocytes by Inhibiting TGFβ Signaling.

Author information

1
Department of Biology, San Diego State University, San Diego, CA, USA.

Abstract

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 telomere length is the transforming growth factor beta (TGFβ) signaling pathway where inhibiting TGFβ signaling 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 signaling 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 signaling 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 signaling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes.

CONCLUSIONS:

Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of TERT. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.

TRANSLATIONAL PERSPECTIVE:

Telomere maintenance is associated with preservation of cardiomyocyte functional competency and survival, with telomeric shortening linked to cardiomyopathic disease. Aging also contributes to telomere erosion that contributes to deterioration of myocardial performance. Pim1 kinase mediates beneficial effects to preserve cardiomyocyte survival and function and this report demonstrates a novel molecular mechanism of Pim1 action to mitigate telomeric shortening. Findings linking Pim1 to telomere biology introduce another facet of cardioprotection that can be developed as a molecular interventional approach to treat myocardial injury and heart failure.

KEYWORDS:

Pim1; Smad2; TGFβ; Telomere; cardiomyocyte

PMID:
32176281
DOI:
10.1093/cvr/cvaa066

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center