Identification of Metabolic Pathways Underlying FGF1 and CHIR99021-mediated Cardioprotection

Overview

Journal iScience

Publisher Cell Press

Date 2022 Jun 16

PMID 35707727

Authors

Bing Xu

Fan Li

Wenjing Zhang

Yajuan Su

Ling Tang

Pengsheng Li

Jyotsna Joshi

Aaron Yang

Dong Li

Zhao Wang

Shu Wang

Jingwei Xie

Haiwei Gu

Wuqiang Zhu

Affiliations

Soon will be listed here.

Abstract

Acute myocardial infarction is a leading cause of death worldwide. We have previously identified two cardioprotective molecules - FGF1 and CHIR99021- that confer cardioprotection in mouse and pig models of acute myocardial infarction. Here, we aimed to determine if improved myocardial metabolism contributes to this cardioprotection. Nanofibers loaded with FGF1 and CHIR99021 were intramyocardially injected to ischemic myocardium of adult mice immediately following surgically induced myocardial infarction. Animals were euthanized 3 and 7 days later. Our data suggested that FGF1/CHIR99021 nanofibers enhanced the heart's capacity to utilize glycolysis as an energy source and reduced the accumulation of branched-chain amino acids in ischemic myocardium. The impact of FGF1/CHIR99021 on metabolism was more obvious in the first three days post myocardial infarction. Taken together, these findings suggest that FGF1/CHIR99021 protects the heart against ischemic injury via improving myocardial metabolism which may be exploited for treatment of acute myocardial infarction in humans.

Citing Articles

Exploration and verification of the therapeutic mechanism of shenfu injection in sepsis-induced myocardial injury.

Yuan H, Xiang G, Liu Y, Li Y, Liu W, Wei J PLoS One. 2025; 20(1):e0317738.

PMID: 39823512 PMC: 11741597. DOI: 10.1371/journal.pone.0317738.

Microparticle Mediated Delivery of Apelin Improves Heart Function in Post Myocardial Infarction Mice.

Tang L, Qiu H, Xu B, Su Y, Nyarige V, Li P Circ Res. 2024; 135(7):777-798.

PMID: 39145385 PMC: 11392624. DOI: 10.1161/CIRCRESAHA.124.324608.

Peptide-Guided Nanoparticle Drug Delivery for Cardiomyocytes.

Li D, Taylor A, Shi H, Zhou F, Li P, Joshi J Biology (Basel). 2024; 13(1).

PMID: 38248477 PMC: 10812947. DOI: 10.3390/biology13010047.

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review.

Shafi O, Siddiqui G, Jaffry H BMC Cancer. 2023; 23(1):1245.

PMID: 38110859 PMC: 10726542. DOI: 10.1186/s12885-023-11723-3.

Identification of the metabolic state of surviving cardiomyocytes in the human infarcted heart by spatial single-cell transcriptomics.

Shen Y, Kim I, Weintraub N, Tang Y Cardiol Plus. 2023; 8(1):18-26.

PMID: 37187809 PMC: 10180026. DOI: 10.1097/CP9.0000000000000038.

References

Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano T, Sadoshima J . AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy. 2007; 3(4):405-7. DOI: 10.4161/auto.4281. View

York J, PENNEY D, Weeks T, STAGNO P . Lactate dehydrogenase changes following several cardiac hypertrophic stresses. J Appl Physiol. 1976; 40(6):923-6. DOI: 10.1152/jappl.1976.40.6.923. View

Huang C, Liu Y, Beenken A, Jiang L, Gao X, Huang Z . A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration. Cardiovasc Res. 2017; 113(13):1585-1602. PMC: 5852627. DOI: 10.1093/cvr/cvx165. View

Cole J, Sweatt A, Hutson S . Expression of mitochondrial branched-chain aminotransferase and α-keto-acid dehydrogenase in rat brain: implications for neurotransmitter metabolism. Front Neuroanat. 2012; 6:18. PMC: 3361127. DOI: 10.3389/fnana.2012.00018. View

Fernandes P, Kinkead J, McNae I, Michels P, Walkinshaw M . Biochemical and transcript level differences between the three human phosphofructokinases show optimisation of each isoform for specific metabolic niches. Biochem J. 2020; 477(22):4425-4441. PMC: 7702303. DOI: 10.1042/BCJ20200656. View

Islam M, Nautiyal M, Wynn R, Mobley J, Chuang D, Hutson S . Branched-chain amino acid metabolon: interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm). J Biol Chem. 2009; 285(1):265-76. PMC: 2804173. DOI: 10.1074/jbc.M109.048777. View

Baxter G, Hale S, Miki T, Kloner R, Cohen M, Downey J . Adenosine A1 agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study. Cardiovasc Drugs Ther. 2001; 14(6):607-14. DOI: 10.1023/a:1007850527878. View

Jiang J, Chen G, Shuler F, Wang C, Xie J . Local Sustained Delivery of 25-Hydroxyvitamin D3 for Production of Antimicrobial Peptides. Pharm Res. 2015; 32(9):2851-62. PMC: 4529368. DOI: 10.1007/s11095-015-1667-5. View

Suh J, Jonker J, Ahmadian M, Goetz R, Lackey D, Osborn O . Corrigendum: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2015; 520(7547):388. DOI: 10.1038/nature14304. View

10.

Li T, Zhang Z, Kolwicz Jr S, Abell L, Roe N, Kim M . Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. Cell Metab. 2017; 25(2):374-385. PMC: 5301464. DOI: 10.1016/j.cmet.2016.11.005. View

11.

Roczkowsky A, Chan B, Lee T, Mahmud Z, Hartley B, Julien O . Myocardial MMP-2 contributes to SERCA2a proteolysis during cardiac ischaemia-reperfusion injury. Cardiovasc Res. 2019; 116(5):1021-1031. DOI: 10.1093/cvr/cvz207. View

12.

Ying L, Wang L, Guo K, Hou Y, Li N, Wang S . Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects. Nat Commun. 2021; 12(1):7256. PMC: 8671394. DOI: 10.1038/s41467-021-27584-y. View

13.

FRITZ P . Rabbit muscle lactate dehydrogenase 5; a regulatory enzyme. Science. 1965; 150(3694):364-6. DOI: 10.1126/science.150.3694.364. View

14.

Fan C, Tang Y, Zhao M, Lou X, Pretorius D, Menasche P . CHIR99021 and fibroblast growth factor 1 enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice. J Mol Cell Cardiol. 2020; 141:1-10. PMC: 7304478. DOI: 10.1016/j.yjmcc.2020.03.003. View

15.

Lopaschuk G, Karwi Q, Tian R, Wende A, Abel E . Cardiac Energy Metabolism in Heart Failure. Circ Res. 2021; 128(10):1487-1513. PMC: 8136750. DOI: 10.1161/CIRCRESAHA.121.318241. View

16.

Dai C, Li Q, May H, Li C, Zhang G, Sharma G . Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress. Cell Rep. 2020; 32(9):108087. PMC: 7520916. DOI: 10.1016/j.celrep.2020.108087. View

17.

Lopaschuk G, Belke D, Gamble J, Itoi T, Schonekess B . Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta. 1994; 1213(3):263-76. DOI: 10.1016/0005-2760(94)00082-4. View

18.

Shao D, Villet O, Zhang Z, Choi S, Yan J, Ritterhoff J . Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nat Commun. 2018; 9(1):2935. PMC: 6062555. DOI: 10.1038/s41467-018-05362-7. View

19.

Wang J, Liu B, Han H, Yuan Q, Xue M, Xu F . Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction. Mol Med. 2015; 21:68-76. PMC: 4461577. DOI: 10.2119/molmed.2014.00240. View

20.

Tran D, Wang Z . Glucose Metabolism in Cardiac Hypertrophy and Heart Failure. J Am Heart Assoc. 2019; 8(12):e012673. PMC: 6645632. DOI: 10.1161/JAHA.119.012673. View