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Original article
Submitted: 2023-03-23
Accepted: 2023-05-13
Published online: 2023-06-05
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GPR43 protects human A16 cardiomyocytes against hypoxia/reoxygenation injury by regulating nesfatin1

Jie Yu1, Qingquan Li1, Chang Guan1, Ming Yuan1, Ding Yu1, Yaqin Wang1, Mengyao Liu1, Ying Lv1
Affiliations
  1. Cardiovascular Care Unit, The First Hospital of Hebei Medical University, Shijiazhuang, China

open access

Ahead of Print
ORIGINAL ARTICLES
Submitted: 2023-03-23
Accepted: 2023-05-13
Published online: 2023-06-05

Abstract

Background: The purpose of this study is to investigate the regulatory role of G coupled-protein receptor 43 (GPR43) during myocardial ischemia/reperfusion (I/R) injury and to explore the relevant molecular mechanism.

Materials and methods: AC16 hypoxia/reoxygenation (H/R) model was established to simulate I/R injury in vitro. Gain- and loss-of-function experiments were conducted to regulate GPR43 or nesfatin1 expression. Cell viability and apoptosis was examined adopting CCK-8 and TUNEL assays. Commercial kits were applied for detecting ROS and inflammatory cytokines. Quantitative real-time PCR (qRT-PCR) and western blotting were conducted to measure the expression level of critical genes and proteins.

Results: GPR43 was downregulated in H/R-mediated AC16 cells. GPR43 overexpression or the GPR43 agonist greatly inhibited H/R-induced cell viability loss, cell apoptosis, and excessive production of ROS and pro-inflammatory cytokines in AC16 cardiomyocytes. Co-immunoprecipitation (Co-IP) assay identified an interaction between GPR43 and nesfatin1, and GPR43 could positively regulate nesfatin1. In addition, the protective role of GPR43 against H/R injury was partly abolished upon nesfatin1 knockdown. Eventually, GPR43 could inhibit H/R-stimulated JNK/P38 MAPK signaling in AC16 cells, which was also hindered by nesfatin1 knockdown.

Conclusions: Our findings demonstrated the protective role of GPR43 against H/R-mediated cardiomyocytes injury through up-regulating nesfatin1, providing a novel target for the prevention and treatment of myocardial I/R injury.

Abstract

Background: The purpose of this study is to investigate the regulatory role of G coupled-protein receptor 43 (GPR43) during myocardial ischemia/reperfusion (I/R) injury and to explore the relevant molecular mechanism.

Materials and methods: AC16 hypoxia/reoxygenation (H/R) model was established to simulate I/R injury in vitro. Gain- and loss-of-function experiments were conducted to regulate GPR43 or nesfatin1 expression. Cell viability and apoptosis was examined adopting CCK-8 and TUNEL assays. Commercial kits were applied for detecting ROS and inflammatory cytokines. Quantitative real-time PCR (qRT-PCR) and western blotting were conducted to measure the expression level of critical genes and proteins.

Results: GPR43 was downregulated in H/R-mediated AC16 cells. GPR43 overexpression or the GPR43 agonist greatly inhibited H/R-induced cell viability loss, cell apoptosis, and excessive production of ROS and pro-inflammatory cytokines in AC16 cardiomyocytes. Co-immunoprecipitation (Co-IP) assay identified an interaction between GPR43 and nesfatin1, and GPR43 could positively regulate nesfatin1. In addition, the protective role of GPR43 against H/R injury was partly abolished upon nesfatin1 knockdown. Eventually, GPR43 could inhibit H/R-stimulated JNK/P38 MAPK signaling in AC16 cells, which was also hindered by nesfatin1 knockdown.

Conclusions: Our findings demonstrated the protective role of GPR43 against H/R-mediated cardiomyocytes injury through up-regulating nesfatin1, providing a novel target for the prevention and treatment of myocardial I/R injury.

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Keywords

hypoxia/reoxygenation, cardiomyocyte, GPR43, nesfatin1

About this article
Title

GPR43 protects human A16 cardiomyocytes against hypoxia/reoxygenation injury by regulating nesfatin1

Journal

Folia Morphologica

Issue

Ahead of Print

Article type

Original article

Published online

2023-06-05

Page views

394

Article views/downloads

249

DOI

10.5603/FM.a2023.0038

Pubmed

37285089

Keywords

hypoxia/reoxygenation
cardiomyocyte
GPR43
nesfatin1

Authors

Jie Yu
Qingquan Li
Chang Guan
Ming Yuan
Ding Yu
Yaqin Wang
Mengyao Liu
Ying Lv

References (37)
  1. Angelone T, Rocca C, Pasqua T. Nesfatin-1 in cardiovascular orchestration: from bench to bedside. Pharmacol Res. 2020; 156: 104766.
  2. Bagheri F, Khori V, Alizadeh AM, et al. Reactive oxygen species-mediated cardiac-reperfusion injury: mechanisms and therapies. Life Sci. 2016; 165: 43–55.
  3. Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: physiopathological relevance and therapeutic prospects. Trends Pharmacol Sci. 2013; 34(4): 226–232.
  4. Blanco AM, Velasco C, Bertucci JI, et al. Nesfatin-1 regulates feeding, glucosensing and lipid metabolism in rainbow trout. Front Endocrinol (Lausanne). 2018; 9: 484.
  5. Chamberlain JJ, Johnson EL, Leal S, et al. Cardiovascular disease and risk management: review of the american diabetes association standards of medical care in diabetes 2018. Ann Intern Med. 2018; 168(9): 640–650.
  6. Goebel-Stengel M, Stengel A. Role of brain NUCB2/nesfatin-1 in the stress-induced modulation of gastrointestinal functions. Curr Neuropharmacol. 2016; 14(8): 882–891.
  7. Hu J, Kyrou I, Tan BK, et al. Short-chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes. Endocrinology. 2016; 157(5): 1881–1894.
  8. Huang G, Lu X, Duan Z, et al. PCSK9 knockdown can improve myocardial ischemia/reperfusion injury by inhibiting autophagy. Cardiovasc Toxicol. 2022; 22(12): 951–961.
  9. Huang W, Man Yi, Gao C, et al. Short-Chain fatty acids ameliorate diabetic nephropathy via GPR43-mediated inhibition of oxidative stress and NF-B signaling. Oxid Med Cell Longev. 2020; 2020: 4074832.
  10. Jiang X, Zhang Y, Zhang H, et al. Acetate suppresses myocardial contraction via the short-chain fatty acid receptor GPR43. Front Physiol. 2022; 13: 1111156.
  11. Li SY, Li ZX, He ZG, et al. Quantitative proteomics reveal the alterations in the spinal cord after myocardial ischemia‑reperfusion injury in rats. Int J Mol Med. 2019; 44(5): 1877–1887.
  12. Li Z, Gao L, Tang H, et al. Peripheral effects of nesfatin-1 on glucose homeostasis. PLoS One. 2013; 8(8): e71513.
  13. Lu X, Qiao S, Peng C, et al. Bornlisy attenuates colitis-associated colorectal cancer via inhibiting GPR43-mediated glycolysis. Front Nutr. 2021; 8: 706382.
  14. Lymperopoulos A, Suster MS, Borges JI. Short-chain fatty acid receptors and cardiovascular function. Int J Mol Sci. 2022; 23(6).
  15. Maneechote C, Palee S, Chattipakorn SC, et al. Roles of mitochondrial dynamics modulators in cardiac ischaemia/reperfusion injury. J Cell Mol Med. 2017; 21(11): 2643–2653.
  16. McKenzie CI, Mackay CR, Macia L. GPR43 — a prototypic metabolite sensor linking metabolic and inflammatory diseases. Trends Endocrinol Metab. 2015; 26(10): 511–512.
  17. Naseroleslami M, Sharifi M, Rakhshan K, et al. and Aboutaleb N: Nesfatin-1 attenuates injury in a rat model of myocardial infarction by targeting autophagy, inflammation, and apoptosis. Arch Physiol Biochem. 2023; 129: 122–130.
  18. Nie C, Ding X, A R, et al. Hydrogen gas inhalation alleviates myocardial ischemia-reperfusion injury by the inhibition of oxidative stress and NLRP3-mediated pyroptosis in rats. Life Sci. 2021; 272: 119248.
  19. Oh IS, Shimizu H, Satoh T, et al. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006; 443(7112): 709–712.
  20. Park BO, Kang JS, Paudel S, et al. Novel GPR43 agonists exert an anti-inflammatory effect in a colitis model. Biomol Ther (Seoul). 2022; 30(1): 48–54.
  21. Ruan J, Meng H, Wang X, et al. and meng F: low expression of FFAR2 in peripheral white blood cells may be a genetic marker for early diagnosis of acute myocardial infarction. Cardiol Res Pract. 2020; 3108124: 2020.
  22. Senga T, Iwamoto S, Yoshida T, et al. LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood. 2003; 101(3): 1185–1187.
  23. Su RY, Geng XY, Yang Y, et al. Nesfatin-1 inhibits myocardial ischaemia/reperfusion injury through activating Akt/ERK pathway-dependent attenuation of endoplasmic reticulum stress. J Cell Mol Med. 2021; 25(11): 5050–5059.
  24. Tong X, Chen J, Liu W, et al. and Zhu H: LncRNA LSINCT5/miR-222 regulates myocardial ischemia‑reperfusion injury through PI3K/AKT pathway. J Thromb Thrombolysis. 2021; 52: 720–729.
  25. Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 2010; 106(3): 360–368.
  26. Wang R, Wang M, Zhou J, et al. Shuxuening injection protects against myocardial ischemia-reperfusion injury through reducing oxidative stress, inflammation and thrombosis. Ann Transl Med. 2019; 7(20): 562.
  27. White CR, Giordano S, Anantharamaiah GM. High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms. Chem Phys Lipids. 2016; 199: 161–169.
  28. Xiang S, Xiao J, Xiang Mi, et al. Down-regulation of miR-320 exerts protective effects on myocardial I-R injury via facilitating Nrf2 expression. Eur Rev Med Pharmacol Sci. 2019; 23(4): 1730–1741.
  29. Xiao G, Liu J, Wang H, et al. CXCR1 and its downstream NF-κB inflammation signaling pathway as a key target of Guanxinning injection for myocardial ischemia/reperfusion injury. Front Immunol. 2022; 13: 1007341.
  30. Xiao MM, Li JB, Jiang LL, et al. and Wang BL: Plasma nesfatin-1 level is associated with severity of depression in Chinese depressive patients. BMC Psychiatry. 2018; 18(1): 88.
  31. Xu Q, Xu J, Wu Y. Regulation of inflammation and apoptosis by GPR43 via JNK/ELK1 in acute lung injury. Inflamm Res. 2022; 71(5-6): 603–614.
  32. Xu Y, Chen F. Antioxidant, anti-inflammatory and anti-apoptotic activities of Nesfatin-1: a review. J Inflamm Res. 2020; 13: 607–617.
  33. Yang W, Lai Q, Zhang L, et al. Mechanisms dissection of the combination GRS derived from ShengMai preparations for the treatment of myocardial ischemia/reperfusion injury. J Ethnopharmacol. 2021; 264: 113381.
  34. Yousuf T, Nakhle A, Rawal H, et al. Natural disasters and acute myocardial infarction. Prog Cardiovasc Dis. 2020; 63(4): 510–517.
  35. Zhai M, Li B, Duan W, et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 2017; 63(2).
  36. Zhang C, Chang J, Wu W, et al. Activation of GPR43 suppresses TNF-α-induced inflammatory response in human fibroblast-like synoviocytes. Arch Biochem Biophys. 2020; 684: 108297.
  37. Zhao ZQ. Oxidative stress-elicited myocardial apoptosis during reperfusion. Curr Opin Pharmacol. 2004; 4(2): 159–165.

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