Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24215-4
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Funding
- German research foundation [SCHI 1290/1-1]
- National Institutes of Health (NIH) [2R01HL105924]
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The Thbs family of proteins, particularly Thbs1, plays a critical role in regulating adult cardiomyocyte size in the stressed heart through activation of PERK-eIF2 alpha -ATF4-induced autophagy.
The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein production. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiac atrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Antithetically, Thbs1(-/-) mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6 alpha, CD36 or CD47 does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encoding PERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largely corrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9 gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2 alpha -ATF4-induced autophagy as a critical regulator of cardiomyocyte size in the stressed heart. Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2 alpha -ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart.
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