Nicotinamide ribose ameliorates myocardial ischemia/reperfusion injury by regulating autophagy and regulating oxidative stress

Yuan,Chen; Yang,Heng; Lan,Wanqi; Yang,Juesheng; Tang,Yanhua

doi:10.3892/etm.2024.12475

Nicotinamide ribose ameliorates myocardial ischemia/reperfusion injury by regulating autophagy and regulating oxidative stress

Authors:
- Chen Yuan
- Heng Yang
- Wanqi Lan
- Juesheng Yang
- Yanhua Tang
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Affiliations: The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: March 7, 2024 https://doi.org/10.3892/etm.2024.12475
Article Number: 187
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Nicotinamide riboside (NR) has been reported to play a protective role in myocardial ischemia‑reperfusion (I/R) injury when used in association with other drugs; however, the individual effect of NR is unknown. In the present study Evan's blue/triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, echocardiography, western blotting, reverse transcription‑quantitative PCR, and the detection of myocardial injury‑associated markers and oxidative stress metabolites were used to explore the ability of NR to alleviate cardiac I/R injury and the relevant mechanisms of action. In a mouse model of I/R injury, dietary supplementation with NR reduced the area of myocardial ischemic infarction, alleviated pathological myocardial changes, decreased inflammatory cell infiltration and attenuated the levels of mitochondrial reactive oxygen species (ROS) and creatine kinase myocardial band (CK‑MB). In addition, echocardiography suggested that NR alleviated the functional damage of the myocardium caused by I/R injury. In H9c2 cells, NR pretreatment reduced the levels of lactate dehydrogenase, CK‑MB, malondialdehyde, superoxide dismutase and ROS, and reduced cell mortality after the induction of hypoxia/reoxygenation (H/R) injury. In addition, the results indicated NR activated sirt 1 via the upregulation of nicotinamide adenine dinucleotide (NAD⁺) and protected the cells against autophagy. The sirt 1 inhibitor EX527 significantly attenuated the ability of NR to inhibit autophagy, but had no significant effect on the ROS content of the H9c2 cells. In summary, the present study suggests that NR protects against autophagy by increasing the NAD⁺ content in the body via the sirt 1 pathway, although the sirt 1 pathway does not affect oxidative stress.

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1	Writing Group Members. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, et al: Heart disease and stroke statistics-2016 update a report from the American heart association. Circulation. 133:e38–e360. 2016.PubMed/NCBI View Article : Google Scholar
2	Buja LM: Myocardial ischemia and reperfusion injury. Cardiovasc Pathol. 14:170–175. 2005.PubMed/NCBI View Article : Google Scholar
3	Mokhtari-Zaer A, Marefati N, Atkin SL, Butler AE and Sahebkar A: The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol. 234:214–222. 2018.PubMed/NCBI View Article : Google Scholar
4	Hausenloy DJ and Yellon DM: Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest. 123:92–100. 2013.PubMed/NCBI View Article : Google Scholar
5	Yellon DM and Baxter GF: Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: A distant dream or near reality? Heart. 83:381–387. 2000.PubMed/NCBI View Article : Google Scholar
6	Goldhaber JI and Weiss JN: Oxygen free radicals and cardiac reperfusion abnormalities. Hypertension. 20:118–127. 1992.PubMed/NCBI View Article : Google Scholar
7	Collard CD and Gelman S: Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology. 94:1133–1138. 2001.PubMed/NCBI View Article : Google Scholar
8	Burke AP and Virmani R: Pathophysiology of acute myocardial infarction. Med Clin North Am. 91:553–572. 2007.PubMed/NCBI View Article : Google Scholar
9	Becker LB: New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res. 61:461–470. 2004.PubMed/NCBI View Article : Google Scholar
10	Martinet W, Knaapen MW, Kockx MM and De Meyer GR: Autophagy in cardiovascular disease. Trends Mol Med. 13:482–491. 2007.PubMed/NCBI View Article : Google Scholar
11	Ferrari R, Balla C, Malagù M, Guardigli G, Morciano G, Bertini M, Biscaglia S and Campo G: Reperfusion damage-a story of success, failure, and hope. Circ J. 81:131–141. 2017.PubMed/NCBI View Article : Google Scholar
12	Turer AT and Hill JA: Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 106:360–368. 2010.PubMed/NCBI View Article : Google Scholar
13	Moens AL, Claeys MJ, Timmermans JP and Vrints CJ: Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol. 100:179–190. 2005.PubMed/NCBI View Article : Google Scholar
14	Du J, Li Y and Zhao W: Autophagy and myocardial ischemia. Adv Exp Med Biol. 1207:217–222. 2020.PubMed/NCBI View Article : Google Scholar
15	Yorimitsu T and Klionsky DJ: Autophagy: Molecular machinery for self-eating. Cell Death Differ. 12 (Suppl 2):1542–1552. 2005.PubMed/NCBI View Article : Google Scholar
16	Hu S, Cao S, Tong Z and Liu J: FGF21 protects myocardial ischemia-reperfusion injury through reduction of miR-145-mediated autophagy. Am J Transl Res. 10:3677–3688. 2018.PubMed/NCBI
17	Zhang J, Liu J, Huang Y, Chang JY, Liu L, McKeehan WL, Martin JF and Wang F: FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. Circ Res. 110:e29–e39. 2012.PubMed/NCBI View Article : Google Scholar
18	Chambon P, Weill JD and Mandel P: Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun. 11:39–43. 1963.PubMed/NCBI View Article : Google Scholar
19	De Flora A, Zocchi E, Guida L, Franco L and Bruzzone S: Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system. Ann N Y Acad Sci. 1028:176–191. 2004.PubMed/NCBI View Article : Google Scholar
20	Imai S, Armstrong CM, Kaeberlein M and Guarente L: Transcriptional silencing and longevity protein Sir2 is an NAD+-dependent histone deacetylase. Nature. 403:795–800. 2000.PubMed/NCBI View Article : Google Scholar
21	Mehmel M, Jovanović N and Spitz U: Nicotinamide riboside-the current state of research and therapeutic uses. Nutrients. 12(1616)2020.PubMed/NCBI View Article : Google Scholar
22	Luo G, Jian Z, Zhu Y, Zhu Y, Chen B, Ma R, Tang F and Xiao Y: Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress. Int J Mol Med. 43:2033–2043. 2019.PubMed/NCBI View Article : Google Scholar
23	Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, et al: NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 352:1436–1443. 2016.PubMed/NCBI View Article : Google Scholar
24	Lin JH, Yang KT, Ting PC, Luo YP, Lin DJ, Wang YS and Chang JC: Gossypol acetic acid attenuates cardiac ischemia/reperfusion injury in rats via an antiferroptotic mechanism. Biomolecules. 11(1667)2021.PubMed/NCBI View Article : Google Scholar
25	Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, Mattson MP, Croteau DL and Bohr VA: NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proc Natl Acad Sci USA. 118(e2011226118)2021.PubMed/NCBI View Article : Google Scholar
26	Diguet N, Trammell SAJ, Tannous C, Deloux R, Piquereau J, Mougenot N, Gouge A, Gressette M, Manoury B, Blanc J, et al: Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation. 137:2256–2273. 2018.PubMed/NCBI View Article : Google Scholar
27	Sun L, Wang H, Xu D, Yu S, Zhang L and Li X: Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway. Bioengineered. 13:48–60. 2022.PubMed/NCBI View Article : Google Scholar
28	Lu ZY, Liu ZY and Fang B: Propofol protects cardiomyocytes from doxorubicin-induced toxic injury by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 signaling pathways. Bioengineered. 13:9145–9155. 2021.PubMed/NCBI View Article : Google Scholar
29	Donato AJ, Walker AE, Magerko KA, Bramwell RC, Black AD, Henson GD, Lawson BR, Lesniewski LA and Seals DR: Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice. Aging Cell. 12:772–783. 2013.PubMed/NCBI View Article : Google Scholar
30	Donato AJ, Magerko KA, Lawson BR, Durrant JR, Lesniewski LA and Seals DR: SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J Physiol. 589:4545–4554. 2011.PubMed/NCBI View Article : Google Scholar
31	Ding S, Liu D, Wang L, Wang G and Zhu Y: Inhibiting microRNA-29a protects myocardial ischemia-reperfusion injury by targeting SIRT1 and suppressing oxidative stress and NLRP3-mediated pyroptosis pathway. J Pharmacol Exp Ther. 372:128–135. 2020.PubMed/NCBI View Article : Google Scholar
32	Xiao Y, Phelp P, Wang Q, Bakker D, Nederlof R, Hollmann MW and Zuurbier CJ: Cardioprotecive properties of known agents in rat ischemia-reperfusion model under clinically relevant conditions: Only the NAD precursor nicotinamide riboside reduces infarct size in presence of fentanyl, midazolam and cangrelor, but not propofol. Front Cardiovasc Med. 8(712478)2021.PubMed/NCBI View Article : Google Scholar
33	Bogan KL and Brenner C: Nicotinic acid, nicotinamide, and nicotinamide riboside: A molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 28:115–130. 2008.PubMed/NCBI View Article : Google Scholar
34	Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA and Brenner C: Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci Rep. 6(26933)2016.PubMed/NCBI View Article : Google Scholar
35	Houstis N, Rosen ED and Lander ES: Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 440:944–948. 2006.PubMed/NCBI View Article : Google Scholar
36	Xu C, Wang L, Fozouni P, Evjen G, Chandra V, Jiang J, Lu C, Nicastri M, Bretz C, Winkler JD, et al: SIRT1 is downregulated by autophagy in senescence and ageing. Nat Cell Biol. 22:1170–1179. 2020.PubMed/NCBI View Article : Google Scholar
37	Yang M, Xi N, Gao M and Yu Y: Sitagliptin mitigates hypoxia/reoxygenation (H/R)-induced injury in cardiomyocytes by mediating sirtuin 3 (SIRT3) and autophagy. Bioengineered. 13:13162–13173. 2022.PubMed/NCBI View Article : Google Scholar
38	Liu CY, Zhang YH, Li RB, Zhou LY, An T, Zhang RC, Zhai M, Huang Y, Yan KW, Dong YH, et al: LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat Commun. 9(29)2018.PubMed/NCBI View Article : Google Scholar
39	Gao C, Wang R, Li B, Guo Y, Yin T, Xia Y, Zhang F, Lian K, Liu Y, Wang H, et al: TXNIP/Redd1 signalling and excessive autophagy: A novel mechanism of myocardial ischaemia/reperfusion injury in mice. Cardiovasc Res. 116:645–657. 2020.PubMed/NCBI View Article : Google Scholar
40	Marek-Iannucci S, Thomas A, Hou J, Crupi A, Sin J, Taylor DJ, Czer LS, Esmailian F, Mentzer RM Jr, Andres AM and Gottlieb RA: Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury. Sci Rep. 9(10001)2019.PubMed/NCBI View Article : Google Scholar
41	Eltzschig HK and Eckle T: Ischemia and reperfusion-from mechanism to translation. Nat Med. 17:4349–4360. 2011.PubMed/NCBI View Article : Google Scholar
42	Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, et al: Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 515:431–435. 2014.PubMed/NCBI View Article : Google Scholar
43	Cadenas S: ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med. 117:76–89. 2018.PubMed/NCBI View Article : Google Scholar
44	Jin Q, Jiang Y, Fu L, Zheng Y, Ding Y and Liu Q: Wenxin granule ameliorates hypoxia/reoxygenation-induced oxidative stress in mitochondria via the PKC-δ/NOX2/ROS pathway in H9c2 cells. Oxid Med Cell Longev. 2020(3245483)2020.PubMed/NCBI View Article : Google Scholar
45	Sinning C, Westermann D and Clemmensen P: Oxidative stress in ischemia and reperfusion: Current concepts, novel ideas and future perspectives. Biomark Med. 11:11031–1040. 2017.PubMed/NCBI View Article : Google Scholar