Cardiology: A new strategy for cardiac protection

It may be possible to treat cardiac hypertrophy and injury by using drugs that inhibit a protein called SIRT2.
  1. Esmaa Bouhamida
  2. Hina W Chaudhry  Is a corresponding author
  1. Cardiac Regenerative Medicine Laboratory and the Department of Cardiology, Icahn School of Medicine at Mount Sinai, United States

Cardiac hypertrophy is a complicated medical condition that occurs when muscle cells in the heart increase in size in response to pressure overload as they lose the ability to proliferate after birth due to exit from the cell cycle (Chaudhry et al., 2004; Cheng et al., 2007; Mohamed et al., 2018). Cardiac hypertrophy can sometimes arise through physiological adaptation to exercise or pregnancy. However, it can also be pathological – when, for example, it is caused by long-term hypertension – and this can lead to ischemic heart disease, valvular disorders, and heart failure (Frey et al., 2004; Bouhamida et al., 2023; Morciano et al., 2021). Unfortunately, treatment options are limited, and there are relatively few therapies that directly target heart function and remodeling. There is a need, therefore, to better understand the molecular mechanisms that trigger cardiac hypertrophy, so that researchers can develop new therapeutic approaches that can prevent or slow down the development of this condition and the heart diseases it causes.

Now, in eLife, Hossein Ardehali and colleagues at the Northwestern University School of Medicine – including Xiaoyan Yang, Hsiang-Chun Chang and Yuki Tatekoshi as joint first authors – report the results of experiments on mice that shed light on the molecular mechanisms involved in cardiac hypertrophy (Yang et al., 2023). In particular, they focus on the regulation of a transcription factor known as NRF2 by a protein called SIRT2, which is a member of the Sirtuin family of signaling proteins.

Sirtuin proteins are involved in a wide range of cellular processes, such as aging, cell death, inflammation, and mitochondrial biogenesis (Baur et al., 2012; Preyat and Leo, 2013; Pinton et al., 2007). Recent studies have also suggested that SIRT2 has a role in cardiac hypertrophy (Tang et al., 2017) and heart failure (Sarikhani et al., 2018), although the precise nature of this role has remained unclear. Yang et al. employed a range of different molecular biology and immunogenetics methods to verify gene and protein expression levels, and performed a range of in vitro and in vivo studies, including experiments on mice that lacked the genes for SIRT2 and NRF2.

The researchers showed that SIRT2 was expressed in the heart of wild-type mice, and that the expression of SIRT2 was higher in mice that had been subjected to trans-aortic constriction. They also found increased levels of SIRT2 in hearts explanted from patients with end-stage heart failure due to dilated cardiomyopathy, and in hearts from patients with ischemic cardiomyopathy. Moreover, Yang et al. found that mice deficient in the gene for SIRT2 displayed improved cardiac function in response to pressure overload and ischemia/reperfusion injury. These mice also showed reduced levels of various markers for heart failure following cardiac injury: further, this effect was not gender specific.

Consistent with these results, when short interfering RNA was used to downregulate Sirt2 mRNA in in vitro experiments on neonatal cardiac cells taken from rats, the researchers observed a protective effect against stress-induced cell death. Overall, the results suggest that SIRT2 has a detrimental effect when the heart has been subjected to pressure overload or ischemia/reperfusion injury, and that deletion of the gene for SIRT2 protects against cardiac hypertrophy and ischemic injury.

Yang et al. then went on to identify one of the mechanisms by which SIRT2 deficiency helps protect the heart. This mechanism involved NRF2, a transcription factor that activates genes that code for various antioxidative enzymes and other proteins that protect cells against harmful agents. The researchers found that a lack of SIRT2 triggers the activation of this transcription factor, and increases the transfer of NRF2 from the cytoplasm to the cell nucleus, which leads to higher levels of antioxidants being expressed in the nucleus (Figure 1). Moreover, deletion of the gene for NRF2 can reverse the protection provided by the deletion of the gene for SIRT2. Finally, the researchers went on to show that the in vivo administration of AGK2 – a drug that selectively inhibits SIRT2 – improved cardiac remodeling and protected the heart against cardiac hypertrophy.

Sirt2 deletion protects the heart against cardiac hypertrophy and injury.

(A) Pathological cardiac hypertrophy is associated with increased levels of a signaling protein called SIRT2. (B) Deleting the gene for SIRT2 in mice leads to higher levels of a transcription factor called NRF2 in the nucleus; NRF2 then activates various antioxidant proteins that protect the heart against cardiac hypertrophy and ischemic injury. (C). In vivo administration of a drug called AGK2 also protects the heart because it inhibits SIRT2. NRF2: nuclear factor erythroid 2-related factor 2; SIRT2: sirtuin 2.

Image credit: Figure created by EB using BioRender.

The cardioprotective effect of SIRT2 has been the subject of debate and controversy, and the findings by Yang et al. are inconsistent with some previous reports. For example, one study demonstrated that mice with SIRT2 deficiency exhibit enhanced pathological cardiac hypertrophy (Sarikhani et al., 2018), while another reported that SIRT2 deletion induced aging-dependent and angiotensin II-mediated pathological cardiac hypertrophy (Tang et al., 2017). However, Yang et al. demonstrated the deletion of SIRT2 has a cardioprotective effect regardless of whether SIRT2 is deleted from all cells or specifically from those of the heart. Moreover, they provided a new molecular mechanism for the protective effect of SIRT2 deletion, and also identified a potential therapeutic approach through the selective inhibition of SIRT2.

Possible explanations for the differences between previous studies and the latest work could be the genetic background of the mice, the different approaches used to target the gene for SIRT2, or the different methods to mimic cardiac hypertrophy.

References

Article and author information

Author details

  1. Esmaa Bouhamida

    Esmaa Bouhamida is in the Cardiac Regenerative Medicine Laboratory and the Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4683-8864
  2. Hina W Chaudhry

    Hina W Chaudhry is in the Cardiac Regenerative Medicine Laboratory and the Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, United States

    For correspondence
    hina.chaudhry@mssm.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6111-9852

Publication history

  1. Version of Record published: November 2, 2023 (version 1)

Copyright

© 2023, Bouhamida and Chaudhry

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 433
    Page views
  • 36
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Esmaa Bouhamida
  2. Hina W Chaudhry
(2023)
Cardiology: A new strategy for cardiac protection
eLife 12:e93239.
https://doi.org/10.7554/eLife.93239
  1. Further reading

Further reading

    1. Medicine
    Jinjing Chen, Ruoyu Wang ... Jongsook Kemper
    Research Article

    The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (Fincor). We show that Fincor is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of Fincor in dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by Fincor. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, Fincor, contributing to the amelioration of NASH in mice. Fincor may represent a new drug target for addressing metabolic disorders, including NASH.

    1. Cell Biology
    2. Medicine
    Chun Wang, Khushpreet Kaur ... Gabriel Mbalaviele
    Research Article

    Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g. cell-free DNA and ATP) and cytokines (e.g. IL-1β and IL-18). Accordingly, doxorubicin activated the absent in melanoma (AIM2) and NLR family pyrin domain containing 3 (NLRP3) inflammasomes in macrophages and neutrophils, causing inflammatory cell death pyroptosis and NETosis, which correlated with its leukopenic effects. Moreover, the effects of this chemotherapeutic agent on cytokine secretion, cell demise, and bone loss were attenuated to various extent in conditions of AIM2 and/or NLRP3 insufficiency. Thus, we found that inflammasomes are key players in bone loss caused by doxorubicin, a finding that may inspire the development of a tailored adjuvant therapy that preserves the quality of this tissue in patients treated with this class of drugs.