The impact of complement C1q/tumor necrosis factor-related protein 6-mediated cardiomyocyte pyroptosis on myocardial fibrosis in rats with myocardial infarction.

Impacto de la piroptosis de cardiomiocitos mediada por CTRP6 en la fibrosis miocárdica en ratas con infarto de miocardio.

• Qiu Zhang Department of Cardiology, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, JiangSu, China. https://orcid.org/0009-0002-5874-7484
• Xin Chen Department of Cardiology, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, JiangSu, China. https://orcid.org/0009-0005-6572-9323
• Hao Pan Department of Cardiology, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, JiangSu, China. https://orcid.org/0009-0005-4335-9325
• Zengguang Chen Department of Cardiology, The Second People’s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, JiangSu, China. https://orcid.org/0000-0002-0895-3215

DOI: https://doi.org/10.54817/IC.v67n1a02

Keywords: Myocardial Infarction, Pyroptosis, Fibrosis, Inflammatory Response

Abstract

Complement C1q/tumor necrosis factor-related protein 6 (CTRP6) has anti-inflammatory and metabolic regulatory  properties,  but  its role in ameliorating post-myocardial infarction (MI) myocardial fibrosis via pyroptosis inhibition is unclear. This study investigated whether CTRP6 im- proves post-MI myocardial fibrosis and cardiac dysfunction by suppressing car- diomyocyte pyroptosis through the NLRP3/caspase-1/GSDMD pathway. Thirty Sprague-Dawley rats were randomized to sham-operated (Sham), MI model (MI), or CTRP6-treated (MI+CTRP6) groups. MI was induced by left anterior descending coronary artery ligation; MI+CTRP6 rats received daily subcutane- ous recombinant CTRP6 (0.2 mg/kg) from day 3 post-surgery for 28 days. Car- diac function, fibrosis markers, pyroptosis-related proteins, and inflammatory cytokines were assessed via Western blot, Masson staining, and ELISA. CTRP6 expression was lower in MI vs. Sham (p<0.05). CTRP6 treatment restored its expression, reduced fibrosis markers and collagen deposition, and improved cardiac function (p<0.05). It also  downregulated  pro-inflammatory  cytokines and increased anti-inflammatory cytokines (p<0.05). In other  words,  exoge- nous CTRP6 ameliorated fibrosis and cardiac function by directly inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway.

References

Frampton J, Ortengren AR, Zeitler EP. Arrhythmias After Acute Myocardial Infarction. Yale J Biol Med. 2023; 96(1): 83-94. https://doi.org/10.59249/LSWK8578

Salari N, Morddarvanjoghi F, Abdolmaleki A, Rasoulpoor S, Khaleghi AA, Hezarkhani LA, et al. The global prevalence of myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2023; 23(1): 206. https://doi.org/10.1186/s12872-023-03231-w

Kaier TE, Alaour B, Marber M. Cardiac troponin and defining myocardial infarction. Cardiovasc Res. 2021; 117(10):2203-2215. https://doi.org/10.1093/cvr/cvaa331

Weng L, Ye J, Yang F, Jia S, Leng M, Jia B, et al. TGF-beta1/SMAD3 Regulates Programmed Cell Death 5 That Suppresses Cardiac Fibrosis Post-Myocardial Infarction by Inhibiting HDAC3. Circ Res. 2023; 133(3): 237-251. https://doi.org/10.1161/CIRCRESAHA.123.322596

Chai R, Ye Z, Xue W, Shi S, Wei Y, Hu Y, et al. Tanshinone IIA inhibits cardiomyocyte pyroptosis through TLR4/NF-kappaB p65 pathway after acute myocardial infarction. Front Cell Dev Biol. 2023; 11: 1252942. https://doi.org/10.3389/fcell.2023.1252942

Cai S, Zhang B, Huang C, Deng Y, Wang C, Yang Y, et al. CTRP6 protects against ferroptosis to drive lung cancer progression and metastasis by destabilizing SOCS2 and augmenting the xCT/GPX4 pathway. Cancer Lett. 2023; 579: 216465. https://doi.org/10.1016/j.canlet.2023.216465

Xu E, Yin C, Yi X, Liu Y. Knockdown of CTRP6 inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells through regulating the Akt/NF-kappaB pathway. Clin Exp Pharmacol Physiol. 2020; 47(7): 1203-1211. https://doi.org/10.1111/1440-1681.13289

Senthil Kumar J, Mehboob MZ, Lei X. Exploring CTRP6: a biomarker and therapeutic target in metabolic diseases. Am J Physiol Endocrinol Metab. 2025; 328(2): E139-E147. https://doi.org/10.1152/ajpendo.00353.2024

Liang S, Han J, Cheng W, Chen X. C1q/ tumor necrosis factor-related protein-6 exerts protective effects on myocardial ischemia-reperfusion injury through the modulation of the Akt-GSK-3beta-Nrf2 signaling cascade. Int Immunopharmacol. 2023; 115: 109678. https://doi.org/10.1016/j. intimp.2023.109678

Konijnenberg LSF, Luiken TTJ, Veltien A, Uthman L, Kuster CTA, Rodwell L, et al. Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction. Basic Res Cardiol. 2023; 118(1): 2. https://doi.org/10.1007/s00395-022-00974-z

Tabatabaei SA, Fadaei R, Moradi N, Farrokhi V, Vatannejad A, Afrisham R, et al. Circulating levels of C1q/TNF-alpha-related protein 6 (CTRP6) in coronary artery disease and its correlation with inflammatory markers. J Diabetes Metab Disord. 2024; 23(1): 1233-1241. https://doi.org/10.1007/s40200-024-01415-5

Yan S, Ding J, Wang Z, Zhang F, Li J, Zhang Y, et al. CTRP6 regulates M1 macrophage polarization via the PPAR-gamma/NF-kappaB pathway and reprogramming glycolysis in recurrent spontaneous abortion. Int Immunopharmacol. 2023; 124(Pt A): 110840. https://doi.org/10.1016/j.in- timp.2023.110840

Yan S, Ding J, Wang Z, Zhang Y, Xu Y, Jia Y, et al. CTRP6 alleviates endometrial fibrosis by regulating Smad3 pathway in intrauterine adhesion. Biol Reprod. 2024; 111(2): 322-331. https://doi.org/10.1093/biolre/ioae016

Fan T, Zhu N, Li M, Wang Z, Lin X. CTRP6-mediated cardiac protection in heart failure via the AMPK/SIRT1/PGC-1alpha signalling pathway. Exp Physiol. 2024; 109(12):2031-2045. https://doi.org/10.1113/EP092036

Guo Q, Chen X, Chen J, Zheng G, Xie C, Wu H, et al. STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF- kappaB signaling pathway. Cell Death Dis. 2021; 12(1): 13. https://doi.org/10.1038/s41419-020-03341-9

Xie YH, Xiao Y, Huang Q, Hu XF, Gong ZC, Du J. Role of the CTRP6/AMPK pathway in kidney fibrosis through the promotion of fatty acid oxidation. Eur J Pharmacol. 2021; 892: 173755. https://doi.org/10.1016/j.ejphar.2020.173755

Hsu CG, Chavez CL, Zhang C, Sowden M, Yan C, Berk BC. The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis. Cell Death Differ. 2022; 29(9):1790-1803. https://doi.org/10.1038/s41418-022-00966-5

Liu C, Yao K, Tian Q, Guo Y, Wang G, He P, et al. CXCR4-BTK axis mediate pyroptosis and lipid peroxidation in early brain injury after subarachnoid hemorrhage via NLRP3 inflammasome and NF-kappaB pathway. Redox Biol. 2023; 68: 102960. https://doi.org/10.1016/j.redox.2023.102960

Li M, Zhou S, Feng Z, Zhang C. Role of C1q/TNF-Related Protein 6 for the Evaluation of Coronary Heart Disease Associated with Type 2 Diabetes. Ther Clin Risk Manag. 2024; 20: 289-296. https://doi.org/10.2147/TCRM.S464007

Sadeghi A, Fadaei R, Moradi N, Fouani FZ, Roozbehkia M, Zandieh Z, et al. Circulating levels of C1q/TNF-alpha-related protein 6 (CTRP6) in polycystic ovary syndrome. IUBMB Life. 2020; 72(7): 1449-1459. https://doi.org/10.1002/iub.2272