Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 Feb 2024
26 Feb 2024
Historique:
received:
29
05
2023
accepted:
22
01
2024
medline:
27
2
2024
pubmed:
27
2
2024
entrez:
26
2
2024
Statut:
epublish
Résumé
Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018's effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.
Identifiants
pubmed: 38409164
doi: 10.1038/s41467-024-45440-7
pii: 10.1038/s41467-024-45440-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1352Informations de copyright
© 2024. The Author(s).
Références
Omote, K., Verbrugge, F. H. & Borlaug, B. A. Heart failure with preserved ejection fraction: mechanisms and treatment strategies. Annu. Rev. Med. 73, 321–337 (2022).
pubmed: 34379445
doi: 10.1146/annurev-med-042220-022745
Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 79, 1757–1780 (2022).
pubmed: 35379504
doi: 10.1016/j.jacc.2021.12.011
Borlaug, B. A. Evaluation and management of heart failure with preserved ejection fraction. Nat. Rev. Cardiol. 17, 559–573 (2020).
pubmed: 32231333
doi: 10.1038/s41569-020-0363-2
Kumar, A. A., Kelly, D. P. & Chirinos, J. A. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation 139, 1435–1450 (2019).
pubmed: 30856000
pmcid: 6414077
doi: 10.1161/CIRCULATIONAHA.118.036259
Sweeney, M., Corden, B. & Cook, S. A. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol. Med. 12, e10865 (2020).
pubmed: 32955172
pmcid: 7539225
doi: 10.15252/emmm.201910865
Spinale, F. G. & Zile, M. R. Integrating the myocardial matrix into heart failure recognition and management. Circ. Res. 113, 725–738 (2013).
pubmed: 23989715
doi: 10.1161/CIRCRESAHA.113.300309
Zile, M. R. et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131, 1247–1259 (2015).
pubmed: 25637629
pmcid: 4390480
doi: 10.1161/CIRCULATIONAHA.114.013215
Abdellatif, M. et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci. Transl. Med. 13, 580 (2021).
doi: 10.1126/scitranslmed.abd7064
Travers, J. G. et al. HDAC inhibition reverses preexisting diastolic dysfunction and blocks covert extracellular matrix remodeling. Circulation 143, 1874–1890 (2021).
pubmed: 33682427
pmcid: 8884170
doi: 10.1161/CIRCULATIONAHA.120.046462
Wallner, M. et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci. Transl. Med. 12, eaay7205 (2020).
Yang, J. et al. Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy. Sci. Transl. Med. 14, eabl5654 (2022).
pubmed: 35857625
doi: 10.1126/scitranslmed.abl5654
Lopaschuk, G. D. et al. Cardiac energy metabolism in heart failure. Circ. Res. 128, 1487–1513 (2021).
pubmed: 33983836
pmcid: 8136750
doi: 10.1161/CIRCRESAHA.121.318241
Schiattarella, G. G. et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568, 351–356 (2019).
pubmed: 30971818
pmcid: 6635957
doi: 10.1038/s41586-019-1100-z
Savji, N. et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail 6, 701–709 (2018).
pubmed: 30007554
pmcid: 6076337
doi: 10.1016/j.jchf.2018.05.018
Bozkurt, B. et al. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation 134, e535–e578 (2016).
pubmed: 27799274
doi: 10.1161/CIR.0000000000000450
Hahn, V. S. et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation 143, 120–134 (2021).
pubmed: 33118835
doi: 10.1161/CIRCULATIONAHA.120.050498
Paulus, W. J. Unfolding discoveries in heart failure. N. Engl. J. Med. 382, 679–682 (2020).
pubmed: 32053308
doi: 10.1056/NEJMcibr1913825
Anker, S. D. et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N. Engl. J. Med. 385, 1451–1461 (2021).
pubmed: 34449189
doi: 10.1056/NEJMoa2107038
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Zile, M. R., Baicu, C. F. & Gaasch, W. H. Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle. N. Engl. J. Med. 350, 1953–1959 (2004).
pubmed: 15128895
doi: 10.1056/NEJMoa032566
Zaleska, M. et al. The cardiac stress response factor Ms1 can bind to DNA and has a function in the nucleus. PLoS One 10, e0144614 (2015).
pubmed: 26656831
pmcid: 4682817
doi: 10.1371/journal.pone.0144614
Hay, J. M. et al. Transcriptional and post-translational targeting of myocyte stress protein 1 (MS1) by the JNK pathway in cardiac myocytes. J. Mol. Signal 12, 3 (2017).
pubmed: 30210579
pmcid: 5853832
doi: 10.5334/1750-2187-12-3
Su, B. C., Hsu, P. L. & Mo, F. E. CCN1 triggers adaptive autophagy in cardiomyocytes to curb its apoptotic activities. J. Cell Commun. Signal 14, 93–100 (2020).
pubmed: 31659628
doi: 10.1007/s12079-019-00534-6
Soraya, A. S. et al. ATF3 expression in cardiomyocytes and myofibroblasts following transverse aortic constriction displays distinct phenotypes. Int. J. Cardiol. Heart Vasc. 32, 100706 (2021).
pubmed: 33437861
Jeong, M. Y. et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci. Transl. Med. 10, eaao0144 (2018).
Chen, X. et al. Acetylation of SERCA2a, another target for heart failure treatment? Circ. Res. 124, 1285–1287 (2019).
pubmed: 31021723
pmcid: 6564686
doi: 10.1161/CIRCRESAHA.119.315017
Lin, Y. H. et al. Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity. J. Mol. Cell Cardiol. 139, 135–147 (2020).
pubmed: 31981571
pmcid: 7363438
doi: 10.1016/j.yjmcc.2020.01.007
Lin, Y. H. et al. HDAC6 modulates myofibril stiffness and diastolic function of the heart. J. Clin. Investig. 132, e148333 (2022).
Lysyganicz, P. K. et al. Loss of deacetylation enzymes Hdac6 and Sirt2 promotes acetylation of cytoplasmic tubulin, but suppresses axonemal acetylation in zebrafish Cilia. Front. Cell Dev. Biol. 9, 676214 (2021).
pubmed: 34268305
pmcid: 8276265
doi: 10.3389/fcell.2021.676214
Tang, X. et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 136, 2051–2067 (2017).
pubmed: 28947430
pmcid: 5698109
doi: 10.1161/CIRCULATIONAHA.117.028728
Murugasamy, K., Munjal, A. & Sundaresan, N. R. Emerging roles of SIRT3 in cardiac metabolism. Front. Cardiovasc. Med. 9, 850340 (2022).
pubmed: 35369299
pmcid: 8971545
doi: 10.3389/fcvm.2022.850340
Li, Y., Shin, D. & Kwon, S. H. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J. 280, 775–793 (2013).
pubmed: 23181831
doi: 10.1111/febs.12079
Ma, S. et al. SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice. Oxid. Med. Cell Longev. 2017, 4602715 (2017).
pubmed: 28883902
pmcid: 5572590
doi: 10.1155/2017/4602715
Wright, E. M., Loo, D. D. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91, 733–794 (2011).
pubmed: 21527736
doi: 10.1152/physrev.00055.2009
Zhou, L. et al. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J. Cell Biochem. 90, 339–346 (2003).
pubmed: 14505350
doi: 10.1002/jcb.10631
Packer, M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis. Circulation 146, 1383–1405 (2022).
pubmed: 36315602
pmcid: 9624240
doi: 10.1161/CIRCULATIONAHA.122.061732
Yang, J. et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat. Commun. 7, 13710 (2016).
pubmed: 27966531
pmcid: 5171850
doi: 10.1038/ncomms13710
Feyen, D. A. M. et al. Metabolic maturation media improve physiological function of human iPSC-derived cardiomyocytes. Cell Rep. 32, 107925 (2020).
pubmed: 32697997
doi: 10.1016/j.celrep.2020.107925
Chen, S. et al. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018).
pubmed: 30423086
pmcid: 6129281
doi: 10.1093/bioinformatics/bty560
Patro, R. et al. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
pubmed: 28263959
pmcid: 5600148
doi: 10.1038/nmeth.4197
Glickman, M. E., Rao, S. R. & Schultz, M. R. False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J. Clin. Epidemiol. 67, 850–857 (2014).
pubmed: 24831050
doi: 10.1016/j.jclinepi.2014.03.012
Stokes, M. P. et al. Complementary PTM profiling of drug response in human gastric carcinoma by immunoaffinity and IMAC methods with total proteome analysis. Proteomes 3, 160–183 (2015).
pubmed: 28248267
pmcid: 5217380
doi: 10.3390/proteomes3030160
Possemato, A. P. et al. Multiplexed phosphoproteomic profiling using titanium dioxide and immunoaffinity enrichments reveals complementary phosphorylation events. J. Proteome Res 16, 1506–1514 (2017).
pubmed: 28171727
pmcid: 5538569
doi: 10.1021/acs.jproteome.6b00905
Eng, J. K., Jahan, T. A. & Hoopmann, M. R. Comet: an open-source MS/MS sequence database search tool. Proteomics 13, 22–24 (2013).
pubmed: 23148064
doi: 10.1002/pmic.201200439
Beausoleil, S. A. et al. A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. 24, 1285–1292 (2006).
pubmed: 16964243
doi: 10.1038/nbt1240
MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26, 966–968 (2010).
pubmed: 20147306
pmcid: 2844992
doi: 10.1093/bioinformatics/btq054
Snel, B. et al. STRING: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene. Nucleic Acids Res. 28, 3442–3444 (2000).
pubmed: 10982861
pmcid: 110752
doi: 10.1093/nar/28.18.3442
Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543–D552 (2022).
pubmed: 34723319
doi: 10.1093/nar/gkab1038