Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway.

Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway. Research Abstract Details 

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Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway. Abstract Text:

Titins, giant sarcomere proteins with major mechanical/signaling functions, are expressed in 2 main isoform classes in the mammalian heart: N2B (3000 kDa) and N2BA (>3200 kDa). A dramatic isoform switch occurs during cardiac development, from fetal N2BA titin (3700 kDa) expressed before birth to a mix of smaller N2BA/N2B isoforms found postnatally; adult rat hearts almost exclusively have N2B titin. The isoform switch, which can be reversed in chronic human heart failure, alters myocardial distensibility and mechanosignaling. Here we determined factors regulating this switch using, as a model system, primary cardiomyocyte cultures prepared from embryonic rats. In standard culture, the mean N2B percentage initially was 14% and increased by approximately 60% within 1 week, resembling the in vivo switching. The titin isoform transition was independent of endothelin-1-induced myocyte hypertrophy and was not altered by pacing, contractile arrest, or cell stretch; however, it was modestly impaired by decreasing substrate rigidity and strongly dependent on serum components. Angiotensin II significantly promoted the transition. The mean N2B proportion in 1-week-old cultures dropped 20% to 25% in hormone-reduced medium, but addition of 3,5,3'-triiodo-l-thyronine (T3) nearly restored the proportion to that found in standard culture. This T3 effect was not prevented by bisphenol A, a specific inhibitor of the classic genomic pathway of T3 action. In contrast, the titin switch could be stalled by the phosphatidylinositol 3-kinase inhibitor LY294002, which decreased the proportion of N2B mRNA transcripts within hours and suppressed a rapid T3-induced increase in Akt phosphorylation. Also, angiotensin II, but not endothelin-1 or cell stretch, enhanced Akt phosphorylation. Thus, although matrix stiffness modulates developmental titin isoform transitions, these transitions are mainly regulated through phosphatidylinositol 3-kinase/Akt-dependent signaling triggered particularly by T3 via a rapid action pathway.

Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway. Publishing Authors By Initials

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Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Circulation research

VOLUME: 102

Page Numbers: 439-47

Journal Abbreviation: Circ. Res.

ISSN: 1524-4571

DAY: 20

MONTH: 12

YEAR: 2007

Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Thyroid Hormone Regulates Developmental Titin Isoform Transitions via the Phosphatidylinositol-3-Kinase/ AKT Pathway.

AFFILIATION: Physiology and Biophysics Unit, University of Muenster, Schlossplatz 5, D-48149 Muenster, Germany. wlinke@uni-muenster.de.

Country: United States

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