New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis

Xiong,Lie; Hu,Huilin; Zhu,Fuxiang; Shi,Hanqiang; Fan,Xiaoliang; Pan,Sunfeng; Zhu,Feiye; Zhang,Junyong; Yu,Zhongwei; Shi,Yanbo

doi:10.3892/ijmm.2024.5436

New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis

Authors:
- Lie Xiong
- Huilin Hu
- Fuxiang Zhu
- Hanqiang Shi
- Xiaoliang Fan
- Sunfeng Pan
- Feiye Zhu
- Junyong Zhang
- Zhongwei Yu
- Yanbo Shi
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Affiliations: Central Laboratory of Molecular Medicine Center, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Department of Cardiology, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, Zhejiang 314000, P.R. China, Central Laboratory of Molecular Medicine Center, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Department of Clinical Pharmacy, Zhejiang Chinese Medical University Affiliated Jiaxing Traditional Chinese Medicine Hospital, Jiaxing, Zhejiang 314000, P.R. China, Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, Zhejiang 314000, P.R. China, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China, College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
Published online on: October 4, 2024 https://doi.org/10.3892/ijmm.2024.5436
Article Number: 112
Copyright: © Xiong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

SS‑31 is a mitochondria‑targeting antioxidant that exhibits promising therapeutic potential for various diseases; however, its protective effect on diabetic cardiomyopathy (DCM) remains to be elucidated. At present, SS‑31 is considered not only to mitigate cardiolipin oxidative damage, but also to alleviate ferroptosis. The present study aimed to explore SS‑31 as a potential therapeutic strategy for improving DCM by alleviating mitochondria‑dependent ferroptosis. In vitro, H9C2 cells were exposed to 35 mM glucose for 24 h to induce high glucose damage, then were simultaneously treated with 10, 20 or 50 µM SS‑31. In addition, in vivo studies were conducted on diabeticC57BL/6J mice, which were induced to develop DCM over 4 weeks, followed by intraperitoneal injections with 2.5 mg/kg/day SS‑31 for a further 4 weeks. The elevation of serum lactate dehydrogenase and creatine kinase isoenzymes, the reduction of fractional shortening and ejection fraction, the rupture of myocardial fibers and the deposition of collagen indicated the establishment of the DCM mouse model. The results of the present study indicated that SS‑31 effectively alleviated these pathological changes and exhibited significant efficacy in ameliorating mitochondrial dysfunction, such as by promoting adenosine triphosphate generation, improving mitochondrial membrane potential and restoring the mitochondrial ultrastructure. Further experiments suggested that activation of the mitochondrial glutathione (mitoGSH)/mitochondrial glutathione peroxidase 4 (mitoGPX4) pathway and the elimination of mitochondrial ferrous ions may constitute the mechanisms by which SS‑31 treats DCM. Therefore, the present study revealed that mitochondria‑dependent ferroptosis could serve as a pathogenic mechanism of DCM and highlighted that the cardioprotective effects of SS‑31 against DCM involves activation of the mitoGSH/mitoGPX4 pathway. Due to the safety profile and cardiac protective effects of SS‑31, SS‑31 was considered a promising strategy for treating DCM.

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1	Bhagani H, Nasser SA, Dakroub A, El-Yazbi AF, Eid AA, Kobeissy F, Pintus G and Eid AH: The mitochondria: A target of polyphenols in the treatment of diabetic cardiomyopathy. Int J Mol Sci. 21:49622020. View Article : Google Scholar : PubMed/NCBI
2	Jia G, Hill MA and Sowers JR: Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res. 122:624–638. 2018. View Article : Google Scholar : PubMed/NCBI
3	Dillmann WH: Diabetic cardiomyopathy. Circ Res. 124:1160–1162. 2019. View Article : Google Scholar : PubMed/NCBI
4	Zhao X, Liu S, Wang X, Chen Y, Pang P, Yang Q, Lin J, Deng S, Wu S, Fan and Wang B: Diabetic cardiomyopathy: Clinical phenotype and practice. Front Endocrinol (Lausanne). 13:10322682022. View Article : Google Scholar : PubMed/NCBI
5	Fang X, Wang H, Han D, Xie E, Yang X, Wei J, Gu S, Gao F, Zhu N, Yin X, et al: Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA. 116:2672–2680. 2019. View Article : Google Scholar : PubMed/NCBI
6	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–72. 2012. View Article : Google Scholar : PubMed/NCBI
7	Miotto G, Rossetto M, Di Paolo ML, Orian L, Venerando R, Roveri A, Vučković AM, Bosello Travain V, Zaccarin M, Zennaro L, et al: Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 28:1013282020. View Article : Google Scholar
8	Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156(1-2): 317–331. 2014. View Article : Google Scholar : PubMed/NCBI
9	Du S, Shi H, Xiong L, Wang P and Shi Y: Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol (Lausanne). 13:10116692022. View Article : Google Scholar : PubMed/NCBI
10	Anderson EJ, Rodriguez E, Anderson CA, Thayne K, Chitwood WR and Kypson AP: Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am J Physiol Heart Circ Physiol. 300:H118–H124. 2011. View Article : Google Scholar :
11	Giacco F and Brownlee M: Oxidative stress and diabetic complications. Circ Res. 107:1058–70. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB and Jiang X: Role of mitochondria in ferroptosis. Mol Cell. 73:354–363.e3. 2019. View Article : Google Scholar :
13	Imai H, Matsuoka M, Kumagai T, Sakamoto T and Koumura T: Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr Top Microbiol Immunol. 403:143–170. 2017.PubMed/NCBI
14	Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, Ishikita A, Matsushima S, Koumura T, Yamada KI, et al: Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insigh. 5:e1327472020. View Article : Google Scholar
15	Schiller PW, Nguyen TM, Berezowska I, Dupuis S, Weltrowska G, Chung NN and Lemieux C: Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem. 35:895–901. 2000. View Article : Google Scholar : PubMed/NCBI
16	Du X, Zeng Q, Luo Y, He L, Zhao Y, Li N, Han C, Zhang G and Liu W: Application research of novel peptide mitochondrial-targeted antioxidant SS-31 in mitigating mitochondrial dysfunction. Mitochondrion. 75:1018462024. View Article : Google Scholar : PubMed/NCBI
17	Dai DF, Chen T, Szeto H, Nieves-Cintrón M, Kutyavin V, Santana LF and Rabinovitch PS: Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol. 58:73–82. 2011. View Article : Google Scholar : PubMed/NCBI
18	Machiraju P, Wang X, Sabouny R, Huang J, Zhao T, Iqbal F, King M, Prasher D, Lodha A, Jimenez-Tellez N, et al: SS-31 peptide reverses the mitochondrial fragmentation present in fibroblasts from patients with DCMA, a mitochondrial cardiomyopathy. Front Cardiovasc Med. 6:1672019. View Article : Google Scholar : PubMed/NCBI
19	Zhang L, Feng M, Wang X, Zhang H, Ding J, Cheng Z and Qian L: Peptide Szeto-Schiller 31 ameliorates doxorubicin-induced cardiotoxicity by inhibiting the activation of the p38 MAPK signaling pathway. Int J Mol Med. 47:632021. View Article : Google Scholar :
20	Zhang P, Chen Y, Zhang S and Chen G: Mitochondria-related ferroptosis drives cognitive deficits in neonatal mice following sevoflurane administration. Front Med (Lausanne). 9:8870622022. View Article : Google Scholar : PubMed/NCBI
21	Liu X, Wang FY, Chi S, Liu T, Yang HL, Zhong RJ, Li XY and Gao J: Mitochondria-targeting peptide SS-31 attenuates ferroptosis via inhibition of the p38 MAPK signaling pathway in the hippocampus of epileptic rats. Brain Res. 1836:1488822024. View Article : Google Scholar : PubMed/NCBI
22	Zacchigna S, Paldino A, Falcão-Pires I, Daskalopoulos EP, Dal Ferro M, Vodret S, Lesizza P, Cannatà A, Miranda-Silva D, Lourenço AP, et al: Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: A position paper of the ESC Working Group on Myocardial Function. Cardiovasc Res. 117:43–59. 2021. View Article : Google Scholar
23	Martinez AM, Kim A and Yang WS: Detection of ferroptosis by BODIPY™ 581/591 C11. Methods Mol Biol. 2108:125–130. 2020. View Article : Google Scholar
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–8. 2001. View Article : Google Scholar
25	Zhao K, Luo G, Zhao GM, Schiller PW and Szeto HH: Transcellular transport of a highly polar 3+ net charge opioid tetrapeptide. J Pharmacol Exp Ther. 304:425–32. 2003. View Article : Google Scholar
26	Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW and Szeto HH: Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 279:34682–34690. 2004. View Article : Google Scholar : PubMed/NCBI
27	Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD and Szeto HH: The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 24:1250–1261. 2013. View Article : Google Scholar : PubMed/NCBI
28	Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, et al: Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 171:273–285. 2017. View Article : Google Scholar : PubMed/NCBI
29	Park MW, Cha HW, Kim J, Kim JH, Yang H, Yoon S, Boonpraman N, Yi SS, Yoo ID and Moon JS: NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases. Redox Biol. 41:1019472021. View Article : Google Scholar : PubMed/NCBI
30	Conrad M and Sato H: The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): Cystine supplier and beyond. Amino Acids. 42:231–246. 2012. View Article : Google Scholar
31	Imai H, Saito M, Kirai N, Hasegawa J, Konishi K, Hattori H, Nishimura M, Naito S and Nakagawa Y: Identification of the positive regulatory and distinct core regions of promoters, and transcriptional regulation in three types of mouse phospholipid hydroperoxide glutathione peroxidase. J Biochem. 140:573–590. 2006. View Article : Google Scholar : PubMed/NCBI