Multi-omics analysis reveals attenuation of cellular stress by empagliflozin in high glucose-treated human cardiomyocytes.
High glucose
Human cardiomyocytes
Metabolomics
SGLT2i
Type-2-diabetes mellitus
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
23 09 2023
23 09 2023
Historique:
received:
09
08
2023
accepted:
16
09
2023
medline:
25
9
2023
pubmed:
24
9
2023
entrez:
23
9
2023
Statut:
epublish
Résumé
Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute the gold standard treatment for type 2 diabetes mellitus (T2DM). Among them, empagliflozin (EMPA) has shown beneficial effects against heart failure. Because cardiovascular diseases (mainly diabetic cardiomyopathy) are the leading cause of death in diabetic patients, the use of EMPA could be, simultaneously, cardioprotective and antidiabetic, reducing the risk of death from cardiovascular causes and decreasing the risk of hospitalization for heart failure in T2DM patients. Interestingly, recent studies have shown that EMPA has positive benefits for people with and without diabetes. This finding broadens the scope of EMPA function beyond glucose regulation alone to include a more intricate metabolic process that is, in part, still unknown. Similarly, this significantly increases the number of people with heart diseases who may be eligible for EMPA treatment. This study aimed to clarify the metabolic effect of EMPA on the human myocardial cell model by using orthogonal metabolomics, lipidomics, and proteomics approaches. The untargeted and multivariate analysis mimicked the fasting blood sugar level of T2DM patients (hyperglycemia: HG) and in the average blood sugar range (normal glucose: NG), with and without the addition of EMPA. Results highlighted that EMPA was able to modulate and partially restore the levels of multiple metabolites associated with cellular stress, which were dysregulated in the HG conditions, such as nicotinamide mononucleotide, glucose-6-phosphate, lactic acid, FA 22:6 as well as nucleotide sugars and purine/pyrimidines. Additionally, EMPA regulated the levels of several lipid sub-classes, in particular dihydroceramide and triacylglycerols, which tend to accumulate in HG conditions resulting in lipotoxicity. Finally, EMPA counteracted the dysregulation of endoplasmic reticulum-derived proteins involved in cellular stress management. These results could suggest an effect of EMPA on different metabolic routes, tending to rescue cardiomyocyte metabolic status towards a healthy phenotype.
Sections du résumé
BACKGROUND
Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute the gold standard treatment for type 2 diabetes mellitus (T2DM). Among them, empagliflozin (EMPA) has shown beneficial effects against heart failure. Because cardiovascular diseases (mainly diabetic cardiomyopathy) are the leading cause of death in diabetic patients, the use of EMPA could be, simultaneously, cardioprotective and antidiabetic, reducing the risk of death from cardiovascular causes and decreasing the risk of hospitalization for heart failure in T2DM patients. Interestingly, recent studies have shown that EMPA has positive benefits for people with and without diabetes. This finding broadens the scope of EMPA function beyond glucose regulation alone to include a more intricate metabolic process that is, in part, still unknown. Similarly, this significantly increases the number of people with heart diseases who may be eligible for EMPA treatment.
METHODS
This study aimed to clarify the metabolic effect of EMPA on the human myocardial cell model by using orthogonal metabolomics, lipidomics, and proteomics approaches. The untargeted and multivariate analysis mimicked the fasting blood sugar level of T2DM patients (hyperglycemia: HG) and in the average blood sugar range (normal glucose: NG), with and without the addition of EMPA.
RESULTS
Results highlighted that EMPA was able to modulate and partially restore the levels of multiple metabolites associated with cellular stress, which were dysregulated in the HG conditions, such as nicotinamide mononucleotide, glucose-6-phosphate, lactic acid, FA 22:6 as well as nucleotide sugars and purine/pyrimidines. Additionally, EMPA regulated the levels of several lipid sub-classes, in particular dihydroceramide and triacylglycerols, which tend to accumulate in HG conditions resulting in lipotoxicity. Finally, EMPA counteracted the dysregulation of endoplasmic reticulum-derived proteins involved in cellular stress management.
CONCLUSIONS
These results could suggest an effect of EMPA on different metabolic routes, tending to rescue cardiomyocyte metabolic status towards a healthy phenotype.
Identifiants
pubmed: 37742032
doi: 10.1186/s12967-023-04537-1
pii: 10.1186/s12967-023-04537-1
pmc: PMC10518098
doi:
Substances chimiques
empagliflozin
HDC1R2M35U
Blood Glucose
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
662Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Curr Probl Cardiol. 2020 Dec;45(12):100406
pubmed: 30704792
Cell Rep. 2021 Mar 16;34(11):108830
pubmed: 33730578
EClinicalMedicine. 2021 Jun 05;36:100933
pubmed: 34308311
Metabolism. 2022 Feb;127:154936
pubmed: 34801581
J Mol Cell Cardiol. 2005 Jul;39(1):133-47
pubmed: 15913645
Metabolites. 2021 Feb 01;11(2):
pubmed: 33535652
Eur Heart J. 2020 Jan 7;41(2):218-220
pubmed: 31605128
JACC Heart Fail. 2021 Aug;9(8):535-549
pubmed: 34325884
Circ Res. 2018 Sep 14;123(7):868-885
pubmed: 30355082
Circulation. 2022 Nov;146(18):1383-1405
pubmed: 36315602
J Lipid Atheroscler. 2019 May;8(1):26-47
pubmed: 32821697
Exp Diabetes Res. 2012;2012:827971
pubmed: 22144992
Sci Rep. 2019 Feb 27;9(1):2892
pubmed: 30814579
EMBO Rep. 2019 Apr;20(4):
pubmed: 30886000
Sci Rep. 2021 May 5;11(1):9544
pubmed: 33953281
J Am Heart Assoc. 2019 Jun 18;8(12):e012673
pubmed: 31185774
Front Cell Dev Biol. 2021 Aug 25;9:706768
pubmed: 34513838
Eur J Pharmacol. 2021 Sep 15;907:174249
pubmed: 34116042
Front Cardiovasc Med. 2020 Jan 08;6:186
pubmed: 31970162
Int J Stroke. 2018 Aug;13(6):612-632
pubmed: 29786478
Sci Rep. 2018 May 1;8(1):6791
pubmed: 29717156
Cardiovasc Res. 2006 Dec 1;72(3):430-7
pubmed: 17034771
Front Physiol. 2021 Aug 06;12:705424
pubmed: 34421642
Cardiovasc Diabetol. 2023 Feb 2;22(1):24
pubmed: 36732760
Cardiovasc Res. 2021 Jan 1;117(1):74-84
pubmed: 32243505
BMC Nurs. 2021 Mar 12;20(1):42
pubmed: 33712001
Circulation. 2022 Sep 13;146(11):808-818
pubmed: 35603596
Circ Res. 2018 Feb 16;122(4):624-638
pubmed: 29449364
Biomolecules. 2022 Apr 04;12(4):
pubmed: 35454131
Front Pharmacol. 2022 Aug 15;13:901340
pubmed: 36046822
J Transl Med. 2015 Sep 12;13:297
pubmed: 26364058
J Clin Med. 2022 Mar 08;11(6):
pubmed: 35329796
Cancers (Basel). 2022 Dec 19;14(24):
pubmed: 36551747
Cardiovasc Diabetol. 2022 Mar 18;21(1):45
pubmed: 35303888
Cell Metab. 2018 Mar 6;27(3):513-528
pubmed: 29249689
Biomed Pharmacother. 2018 Nov;107:306-328
pubmed: 30098549
Nat Rev Cardiol. 2020 Sep;17(9):585-607
pubmed: 32080423
Cardiovasc Diagn Ther. 2021 Feb;11(1):263-276
pubmed: 33708498
J Transl Med. 2023 May 22;21(1):340
pubmed: 37217929
J Transl Med. 2021 Jul 6;19(1):291
pubmed: 34229717
Diabetes Obes Metab. 2020 Jul;22(7):1157-1166
pubmed: 32115853
Front Cardiovasc Med. 2022 Oct 05;9:999254
pubmed: 36277768
Cells. 2020 May 21;9(5):
pubmed: 32455800
Nat Rev Cardiol. 2023 Jul;20(7):443-462
pubmed: 36609604
J Transl Med. 2019 Apr 16;17(1):127
pubmed: 30992077
Circulation. 2018 May 22;137(21):2256-2273
pubmed: 29217642
J Transl Med. 2023 Aug 2;21(1):519
pubmed: 37533007
Clin Exp Pharmacol Physiol. 2021 Jun;48(6):837-845
pubmed: 33527532
PLoS One. 2014 Jan 13;9(1):e85054
pubmed: 24454790
Cureus. 2021 Aug 4;13(8):e16868
pubmed: 34513443
Int J Mol Sci. 2022 Jul 19;23(14):
pubmed: 35887308
J Transl Med. 2023 Feb 1;21(1):66
pubmed: 36726122
Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2207-2216
pubmed: 30354257
J Mol Cell Cardiol. 2022 Jun;167:17-31
pubmed: 35331696
J Am Heart Assoc. 2021 Mar 16;10(6):e018298
pubmed: 33719499
Diabetol Metab Syndr. 2017 Jul 20;9:56
pubmed: 28736579
Circulation. 2007 Sep 4;116(10):1170-5
pubmed: 17698735
Card Fail Rev. 2018 Aug;4(2):99-103
pubmed: 30206484
Nat Commun. 2022 Feb 17;13(1):936
pubmed: 35177612
Circ Res. 2019 Jan 4;124(1):121-141
pubmed: 30605420
BMJ Open. 2022 Aug 11;12(8):e054100
pubmed: 35953245
Eur Heart J. 2020 Jan 7;41(2):209-217
pubmed: 31504427
Cell Metab. 2011 Oct 5;14(4):528-36
pubmed: 21982712
Front Cardiovasc Med. 2022 Jan 10;8:768214
pubmed: 35083298
Angiogenesis. 2021 Aug;24(3):417-433
pubmed: 33548004
Curr Res Physiol. 2022 May 28;5:232-239
pubmed: 35677213
Circ Heart Fail. 2010 May;3(3):420-30
pubmed: 20176713
Eur J Med Chem. 2022 Apr 15;234:114233
pubmed: 35286926
Diabetol Metab Syndr. 2023 Mar 4;15(1):35
pubmed: 36871006
J Chromatogr A. 2022 Jun 21;1673:463124
pubmed: 35567813