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- Title
Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.
- Authors
Coulis, Gérald; Londhe, Avinash D.; Sagabala, R. Sudheer; Shi, Yanfen; Labbé, David P.; Bergeron, Alexandre; Sahadevan, Pramod; Nawaito, Sherin A.; Sahmi, Fatiha; Josse, Marie; Vinette, Valérie; Guertin, Marie-Claude; Karsenty, Gérard; Tremblay, Michel L.; Tardif, Jean-Claude; Allen, Bruce G.; Boivin, Benoit
- 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. Protecting the heart with PTP1B: Pressure overload induced by aortic banding causes oxidative stress. Coulis et al. uncovered a pathway by which oxidative stress exacerbates cardiac hypertrophy after aortic banding. In mice subjected to pressure overload, the tyrosine phosphatase PTP1B was inactivated by oxidation, resulting in greater phosphorylation and decreased microRNA loading of Ago2, a component of the RNA-induced silencing complex. This ultimately led to enhanced sensitivity to thyroid hormone and increased cardiac hypertrophy. Mice with a cardiomyocyte-specific deletion of PTP1B had greater cardiac hypertrophy after pressure overload, an effect blunted by blocking thyroid hormone synthesis. Thus, oxidative stress during pressure overload promotes hypertrophy by inactivating PTP1B, altering microRNA processing, and increasing sensitivity to thyroid hormone.
- Subjects
THYROID hormone receptors; PROTEIN-tyrosine phosphatase; CARDIAC hypertrophy; PHOSPHOPROTEIN phosphatases; THYROID hormones; HORMONE synthesis
- Publication
Science Signaling, 2022, Vol 15, Issue 730, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abn6875