JMJD6 protects against isoproterenol-induced cardiac hypertrophy via inhibition of NF-κB activation by demethylating R149 of the p65 subunit

by Selleckchem | Jun 25 2023

Histone modification plays an important role in pathological cardiac hypertrophy and heart failure. In this study we investigated the role of a histone arginine demethylase, Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy. Cardiac hypertrophy was induced in rats by subcutaneous injection of isoproterenol (ISO, 1.2 mg·kg-1·d-1) for a week. At the end of the experiment, the rats underwent echocardiography, followed by euthanasia and heart collection. We found that JMJD6 levels were compensatorily increased in ISO-induced hypertrophic cardiac tissues, but reduced in patients with heart failure with reduced ejection fraction (HFrEF). Furthermore, we demonstrated that JMJD6 overexpression significantly attenuated ISO-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) evidenced by the decreased cardiomyocyte surface area and hypertrophic genes expression. Cardiac-specific JMJD6 overexpression in rats protected the hearts against ISO-induced cardiac hypertrophy and fibrosis, and rescued cardiac function. Conversely, depletion of JMJD6 by single-guide RNA (sgRNA) exacerbated ISO-induced hypertrophic responses in NRCMs. We revealed that JMJD6 interacted with NF-κB p65 in cytoplasm and reduced nuclear levels of p65 under hypertrophic stimulation in vivo and in vitro. Mechanistically, JMJD6 bound to p65 and demethylated p65 at the R149 residue to inhibit the nuclear translocation of p65, thus inactivating NF-κB signaling and protecting against pathological cardiac hypertrophy. In addition, we found that JMJD6 demethylated histone H3R8, which might be a new histone substrate of JMJD6. These results suggest that JMJD6 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Comments:

The study you described investigates the role of a specific protein called Jumonji C domain-containing protein 6 (JMJD6) in pathological cardiac hypertrophy and its potential as a therapeutic target for heart failure. Cardiac hypertrophy refers to the enlargement of the heart muscle due to various factors, and it is often associated with heart failure, a condition where the heart is unable to pump blood effectively.

In the study, the researchers induced cardiac hypertrophy in rats by injecting them with isoproterenol (ISO) for a week. They observed that levels of JMJD6 were increased in the hypertrophic cardiac tissues of these rats. On the other hand, when they examined patients with heart failure with reduced ejection fraction (HFrEF), they found reduced levels of JMJD6. These findings suggest a compensatory response in cardiac hypertrophy and a potential role of JMJD6 in heart failure.

To further investigate the role of JMJD6, the researchers conducted experiments using neonatal rat cardiomyocytes (NRCMs). They overexpressed JMJD6 in these cells and found that it significantly attenuated the hypertrophic response induced by ISO. This was evidenced by a decrease in cardiomyocyte surface area and a reduction in the expression of hypertrophic genes. Moreover, when they overexpressed JMJD6 specifically in the hearts of rats, it protected against ISO-induced cardiac hypertrophy and fibrosis, and improved cardiac function.

Conversely, when the researchers depleted JMJD6 using single-guide RNA (sgRNA) in NRCMs, it exacerbated the hypertrophic response to ISO. These findings further support the protective role of JMJD6 against pathological cardiac hypertrophy.

The study also investigated the molecular mechanisms underlying the protective effects of JMJD6. The researchers found that JMJD6 interacted with a protein called NF-κB p65 in the cytoplasm, and this interaction reduced the nuclear levels of p65 under hypertrophic stimulation. By binding to p65, JMJD6 demethylated it at a specific residue (R149), thereby inhibiting its nuclear translocation. This inactivation of NF-κB signaling contributed to the protection against pathological cardiac hypertrophy.

Additionally, the researchers discovered that JMJD6 can demethylate a specific residue (H3R8) on a histone protein, which suggests a potential new histone substrate for JMJD6.

Overall, the findings of this study suggest that JMJD6 plays an important role in pathological cardiac hypertrophy and could serve as a potential target for therapeutic interventions in cardiac hypertrophy and heart failure. By inhibiting NF-κB signaling and modulating histone modifications, JMJD6 may offer a novel approach to mitigating the adverse effects of cardiac hypertrophy and improving heart function.