Sodium pump subunit NKAα1 protects against diabetic endothelial dysfunction by inhibiting ferroptosis through the autophagy-lysosome degradation of ACSL4

Abstract

	•NKAα1 downregulation impairs endothelial function in diabetes by promoting oxidative/nitrative stress and ferroptosis.
	•NKAα1 supports lysosomal degradation of ACSL4 via autophagy, preventing lipid peroxidation and ferroptosis.
	•Hamaudol, an activator of NKAα1, restores endothelial relaxation in diabetic mice by inhibiting NKAα1 phosphorylation and endocytosis.

Keywords

diabetes / endothelial dysfunction / ferroptosis autophagy / lysosome / oxidative stress

References

[1] SunHJ, WuZY, NieXW, Bian JS. Role of endothelial dysfunction in cardiovascular diseases: the link between inflammation and hydrogen sulfide. Front Pharmacol. 2019; 10: 1568.

[2] SunHJ, NiZR, LiuY, et al. Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice. Cardiovasc Diabetol. 2024; 23: 138.

[3] VergèsB. Cardiovascular disease in type 1 diabetes, an underestimated danger: epidemiological and pathophysiological data. Atherosclerosis. 2024; 394: 117158.

[4] Naderi-MeshkinH, Setyaningsih WAW. Endothelial cell dysfunction: onset, progression, and consequences. Front Biosci (Landmark edition). 2024; 29: 223.

[5] WangZC, NiuKM, WuYJ, DuKR, QiLW. A dual Keap1 and p47(phox) inhibitor Ginsenoside Rb1 ameliorates high glucose/ox-LDL-induced endothelial cell injury and atherosclerosis. Cell Death Dis. 2022; 13: 824.

[6] ZhangJR, SunHJ. Roles of circular RNAs in diabetic complications: from molecular mechanisms to therapeutic potential. Gene. 2020; 763: 145066.

[7] SunHJ, XiongSP. Hydrogen sulfide in diabetic complications revisited: the state of the art, challenges, and future directions. Antioxid Redox Signal. 2023; 38: 18-44.

[8] SunHJ, WuZY, NieXW, Wang XY, BianJS. An updated insight into molecular mechanism of hydrogen sulfide in cardiomyopathy and myocardial ischemia/reperfusion injury under diabetes. Front Pharmacol. 2021; 12: 651884.

[9] SunHJ, HouB, WangX, Zhu XX, LiKX, QiuLY. Endothelial dysfunction and cardiometabolic diseases: role of long non-coding RNAs. Life Sci. 2016; 167: 6-11.

[10] MiaoG, ZhaoH, GuoK, ChengJ, ZhangS, Zhang X, CaiZ, MiaoH, ShangY. Mechanisms underlying attenuation of apoptosis of cortical neurons in the hypoxic brain by flavonoids from the stems and leaves of Scutellaria baicalensis Georgi. Neural Regen Res. 2014; 9: 1592-1598.

[11] ZhangX, LeeW, BianJS. Recent advances in the study of Na(+)/K(+)-ATPase in neurodegenerative diseases. Cells. 2022:11;4075.

[12] HuangS, DongW, LinX, BianJ. Na+/K+-ATPase: ion pump, signal transducer, or cytoprotective protein, and novel biological functions. Neural Regen Res. 2024; 19: 2684-2697.

[13] SunHJ, TanJX, ShanXD, et al. DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice. Metabolism. 2023; 145: 155579.

[14] LengB, DengL, TanJ, et al. Targeting the Na(+)/K(+) ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity. Free Radical Biol Med. 2023; 204: 38-53.

[15] HuangS, DongW, LinX, et al. Disruption of the Na(+)/K(+)-ATPase-purinergic P2×7 receptor complex in microglia promotes stress-induced anxiety. Immunity. 2024; 57: 495-512. e11.

[16] ZhangX, LiG, ChenH, Nie XW, BianJS. Targeting NKAα1 to treat Parkinson’s disease through inhibition of mitophagy-dependent ferroptosis. Free Radical Biol Med. 2024; 218: 190-204.

[17] ZhuM, CaoL, XiongS, Sun H, WuZ, BianJS. Na(+)/K(+)-ATPase-dependent autophagy protects brain against ischemic injury. Signal Transduct Target Ther. 2020; 5: 55.

[18] PulgarVM, Jeffers AB, RashadHM, DizDI, AileruAA. Increased constrictor tone induced by ouabain treatment in rats. J Cardiovasc Pharmacol. 2013; 62: 174-183.

[19] CuiX, LiuX, FengH, Zhao S, GaoH. Grape seed proanthocyanidin extracts enhance endothelial nitric oxide synthase expression through 5′-AMP activated protein kinase/Surtuin 1-Krüpple like factor 2 pathway and modulate blood pressure in ouabain induced hypertensive rats. Biol Pharm Bull. 2012; 35: 2192-2197.

[20] PagánRM, PrietoD, HernándezM, et al. Regulation of NO-dependent acetylcholine relaxation by K+ channels and the Na+-K+ ATPase pump in porcine internal mammary artery. Eur J Pharmacol. 2010; 641: 61-66.

[21] BondarenkoA, SagachV. Na+-K+-ATPase is involved in the sustained ACh-induced hyperpolarization of endothelial cells from rat aorta. Br J Pharmacol. 2006; 149: 958-965.

[22] FiorimJ, Ribeiro RF Jr, AzevedoBF, et al. Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats. Toxicol Appl Pharmacol. 2012; 262: 22-31.

[23] LiuQ, LiuCQ, YiWZ, et al. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy. Am J Pathol. 2024; 194: 1078-1089.

[24] LuoEF, LiHX, QinYH, et al. Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World J Diab. 2021; 12: 124-137.

[25] YanB, BelkeD, GuiY, ChenYX, JiangZS, Zheng XL. Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells. Cell Death Discov. 2023; 9: 456.

[26] JamesPF, GruppIL, GruppG, et al. Identification of a specific role for the Na, K-ATPase alpha 2 isoform as a regulator of calcium in the heart. Mol Cell. 1999; 3: 555-563.

[27] SunHJ, CaoL, ZhuMY, et al. DR-region of Na(+)/K(+)-ATPase is a target to ameliorate hepatic insulin resistance in obese diabetic mice. Theranostics. 2020; 10: 6149-6166.

[28] TianXY, WongWT, XuA, et al. Uncoupling protein-2 protects endothelial function in diet-induced obese mice. Circ Res. 2012; 110: 1211-1216.

[29] LiZ, LiS, HuL, LiF, et al. Mechanisms underlying action of xinmailong injection, a traditional Chinese medicine in cardiac function improvement. Afr J Trad, Complemen, Alternat Med. 2017; 14: 241-252.

[30] MagidR, Martinson D, HwangJ, JoH, GalisZS. Optimization of isolation and functional characterization of primary murine aortic endothelial cells. Endothelium. 2003; 10: 103-109.

[31] LuoJY, ChengCK, HeL, PuY, ZhangY, Lin X. Endothelial UCP2 is a mechanosensitive suppressor of atherosclerosis. Circ Res. 2022; 131: 424-441.

[32] ZhuXX, MengXY, ChenG, et al. Nesfatin-1 enhances vascular smooth muscle calcification through facilitating BMP-2 osteogenic signaling. Cell Commun Signal. 2024; 22: 488.

[33] RenXS, TongY, QiuY, et al. MiR155-5p in adventitial fibroblasts-derived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing angiotensin-converting enzyme expression. J Extracell Vesicles. 2020; 9: 1698795.

[34] SunHJ, RenXS, XiongXQ, et al. NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension. Cell Death Dis. 2017; 8: e3074.

[35] SymonsJD, McMillin SL, RiehleC, et al. Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res. 2009; 104: 1085-1094.

[36] SunHJ, ChenD, WangPY, et al. Salusin-β is involved in diabetes mellitus-induced endothelial dysfunction via degradation of peroxisome proliferator-activated receptor gamma. Oxid Med Cell Longev. 2017; 2017: 6905217.

[37] ZhuQ, HanY, HeY, et al. Quercetin inhibits neuronal Ferroptosis and promotes immune response by targeting lipid metabolism-related gene PTGS2 to alleviate breast cancer-related depression. Phytomedicine. 2024; 130: 155560.

[38] ZhangK, WuY, ChenG, Wang H, LiuY, ZhouY. Heat shock protein 27 deficiency promotes ferrous ion absorption and enhances acyl-Coenzyme A synthetase long-chain family member 4 stability to promote glioblastoma cell ferroptosis. Cancer Cell Int. 2023; 23: 5.

[39] HuangQ, RuY. Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases. Sci Adv. 2024; 10: eadk1200.

[40] LuQB, DuQ, WangHP, Tang ZH, WangYB, SunHJ. Salusin-β mediates tubular cell apoptosis in acute kidney injury: involvement of the PKC/ROS signaling pathway. Redox Biol. 2020; 30: 101411.

[41] ShangguanJ, LiuG, XiaoL, Zhang W, ZhuX, LiL. Meteorin like/meteorin-β protects against cardiac dysfunction after myocardial infarction in mice by inhibiting autophagy. Exp Therap Med. 2024; 28: 293.

[42] XueL, XuF, MengL, et al. Acetylation-dependent regulation of mitochondrial ALDH2 activation by SIRT3 mediates acute ethanol-induced eNOS activation. FEBS Lett. 2012; 586: 137-142.

[43] ZhuW, YangB, FuH, et al. Flavone inhibits nitric oxide synthase (NOS) activity, nitric oxide production and protein S-nitrosylation in breast cancer cells. Biochem Biophys Res Commun. 2015; 458: 590-595.

[44] BaoMH, LiJM, LuoHQ, et al. NF-κB-regulated miR-99a modulates endothelial cell inflammation. Mediators Inflamm. 2016; 2016: 5308170.

[45] SunH, ZhuX, ZhouY, Cai W, QiuL. C1q/TNF-related protein-9 ameliorates Ox-LDL-induced endothelial dysfunction via PGC-1α/AMPK-mediated antioxidant enzyme induction. Int J Mol Sci. 2017; 18.

[46] JungS, Myagmarjav D, JoT, et al. Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation. Int J Biol Sci. 2022; 18: 3859-3873.

[47] DongL, XieJ, WangY, et al. Mannose ameliorates experimental colitis by protecting intestinal barrier integrity. Nat Commun. 2022; 13: 4804.

[48] ZhuXX, FuX, MengXY, et al. Gut microbiome and metabolites mediate the benefits of caloric restriction in mice after acute kidney injury. Redox Biol. 2024; 77: 103373.

[49] CaoL, XiongS, WuZ, DingL. Anti-Na(+)/K(+)-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na(+)/K(+)-ATPase α1-dependent autophagy. Sci Adv. 2021; 7.

[50] ShenJ, SanW, ZhengY, et al. Different types of cell death in diabetic endothelial dysfunction. Biomed Pharmacother. 2023; 168: 115802.

[51] DollS, Proneth B, TyurinaYY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017; 13: 91-98.

[52] YuanH, LiX, ZhangX, Kang R, TangD. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016; 478: 1338-1343.

[53] PeiZ, LiuY, LiuS, et al. FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis. Metabolism. 2021; 122: 154840.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.