# Role of the Phosphoprotein Phosphatase PTP1B in Cardiac Hypertrophy

> **NIH NIH R15** · SUNY POLYTECHNIC INSTITUTE · 2020 · $449,603

## Abstract

Project Summary
Cardiac hypertrophy occurs when cardiomyocytes are continuously exposed to stresses, such as mechanical
stretch or neurohumoral stimulation. The enlargement is characterized by changes in signaling, gene
expression and electrophysiology that confers short-term benefits; over time, however, the plasticity of the
cardiac muscle in response to these pathological insults predispose individuals to heart failure and mortality.
Hence, there is an urgent need to improve our understanding of the molecular events implicated in the
development of cardiac hypertrophy and of the progression of heart failure in order to identify new therapeutic
targets. Although numerous genetic and pharmacological studies have demonstrated that increased signaling
by cellular oxidants were intimately involved in the progression of cardiac hypertrophy, the molecular
mechanisms whereby oxidants contribute to the progression of hypertrophy are largely unknown. In order to
shed light on these mechanisms, our efforts have focused on protein tyrosine phosphatases (PTPs) and their
distinctive ability to be specifically and reversibly regulated by redox signaling. This research proposal builds
upon our novel observations that oxidation and inactivation of protein tyrosine phosphatase 1B (PTP1B) leads
to phosphorylation and inactivation of its substrate argonaute 2 (Ago2), a key mediator of the biological
functions of microRNAs (miRNAs) in the hypertrophying myocardium. Preliminary data revealed in this
proposal show that PTP1B inactivation by cellular oxidants and by conditional, cardiomyocyte-specific gene
knockout (PTP1B cKO) results in phosphorylation and inactivation of its substrate Ago2, left ventricular
hypertrophy and systolic dysfunction in a thyroid-hormone (T3)-dependent manner. Our in vivo data reveal an
important relationship between PTP1B inactivation and T3 signaling in cardiac hypertrophy that occurs as a
consequence of: defective miRNA-mediated repression of thyroid-hormone receptor-associated protein 1
(THRAP1, known as MED13); a miRNA-independent increase in thyroid-hormone receptor β1 (TRβ1)
expression and; a TRβ1-interaction with p85 the regulatory subunit of phosphatidyl-inositol 3 kinase (PI3K)
when PTP1B is inactivated. These data are consistent with the known T3 regulation of myocardial contractility
and systolic function. We hypothesize that PTP1B inactivation prevents post-transcriptional regulation by
Ago2-miR-208b and profoundly alters T3 signaling in cardiac hypertrophy. We propose that therapeutic
compensation of PTP1B activity will be cardioprotective. We will test our hypothesis by investigating 1) the
interplay between PTP1B and thyroid-hormone signaling in cardiac hypertrophy; 2) the therapeutic
compensation of PTP1B activity in vivo. Understanding how PTP1B integrates redox signaling to regulate
thyroid hormone signaling will facilitate the development of novel therapeutic strategies to control targeted
protein expression and activa...

## Key facts

- **NIH application ID:** 9965175
- **Project number:** 2R15HL138605-02
- **Recipient organization:** SUNY POLYTECHNIC INSTITUTE
- **Principal Investigator:** Benoit Boivin
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,603
- **Award type:** 2
- **Project period:** 2020-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965175

## Citation

> US National Institutes of Health, RePORTER application 9965175, Role of the Phosphoprotein Phosphatase PTP1B in Cardiac Hypertrophy (2R15HL138605-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965175. Licensed CC0.

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