- 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.
Figure 1
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
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Are sirtuins viable targets for improving healthspan and lifespan?Nature Reviews Drug Discovery 11:443–461.https://doi.org/10.1038/nrd3738
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Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardiumJournal of Biological Chemistry 279:35858–35866.https://doi.org/10.1074/jbc.M404975200
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Sirtuin deacylases: A molecular link between metabolism and immunityJournal of Leukocyte Biology 93:669–680.https://doi.org/10.1189/jlb.1112557
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SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasisJournal of Biological Chemistry 293:5281–5294.https://doi.org/10.1074/jbc.RA117.000915
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- Version of Record published: November 2, 2023 (version 1)
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© 2023, Bouhamida and Chaudhry
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Cardiology: A new strategy for cardiac protection
eLife 12:e93239.
https://doi.org/10.7554/eLife.93239
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- Cell Biology
- Medicine
The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor. Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner but failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor in CHO-Glp1r cells. Lean Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss but not setmelanotide-induced (melanocortin-4 receptor-dependent) weight loss. Diet-induced obese Ser791Ala Raptor knock-in mice were not resistant to liraglutide-induced weight loss; however, there was weight-dependent variation such that there was a tendency for obese Ser791Ala Raptor knock-in mice of lower relative body weight to be resistant to liraglutide-induced weight loss compared to weight-matched controls. Together, these findings suggest that PKA-mediated phosphorylation of Raptor at Ser791 contributes to liraglutide-induced weight loss.
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Background:
Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.
Methods:
A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.
Results:
A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.
Conclusions:
Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.
Funding:
This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).
