Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.

Abstract

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.

• Authors: Gérald Coulis, Avinash D Londhe, R Sudheer Sagabala, Yanfen Shi, David P Labbé, Alexandre Bergeron, Pramod Sahadevan, Sherin A Nawaito, Fatiha Sahmi, Marie Josse, Valérie Vinette, Marie-Claude Guertin, Gérard Karsenty, Michel L Tremblay, Jean-Claude Tardif, Bruce G Allen, Benoit Boivin
• Journal: Science signaling (Sci Signal) Vol. 15 Issue 730 Pg. eabn6875 (04 19 2022) ISSN: 1937-9145 [Electronic] United States
• PMID: 35439023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Med13 protein, mouse
• Mediator Complex
• MicroRNAs
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse

Topics

• Animals
• Cardiomegaly (metabolism)
• Mediator Complex
• Mice
• MicroRNAs (genetics, metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (genetics, metabolism)