Asprosin aggravates vascular endothelial dysfunction via disturbing mitochondrial dynamics in obesity models
Yanli Lu
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorWanwan Yuan
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorXiaowei Xiong
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorQianqian Huang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorSheng Chen
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorTingting Yin
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorYanan Zhang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorZhie Wang
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorGuohua Zeng
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorCorresponding Author
Qiren Huang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Correspondence
Qiren Huang, Provincial Key Laboratory of Basic Pharmacology, Nanchang University, 461 Ba-Yi St., Nanchang, 330006, People's Republic of China.
Email: [email protected]
Search for more papers by this authorYanli Lu
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorWanwan Yuan
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorXiaowei Xiong
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorQianqian Huang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorSheng Chen
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorTingting Yin
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorYanan Zhang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorZhie Wang
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorGuohua Zeng
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Search for more papers by this authorCorresponding Author
Qiren Huang
Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
Correspondence
Qiren Huang, Provincial Key Laboratory of Basic Pharmacology, Nanchang University, 461 Ba-Yi St., Nanchang, 330006, People's Republic of China.
Email: [email protected]
Search for more papers by this authorFunding information: Graduate Innovation Fund of Nanchang University, Grant/Award Number: 2021CX238; National Natural Science Foundation of China, Grant/Award Numbers: 81360060, 81960153, 82260726
Abstract
Objective
The aim of the study was to investigate the contribution of asprosin (ASP), a fasting-induced hormone involved in metabolic disorders, to vascular endothelial dysfunction in obesity models.
Methods
Primary rat thoracic aortic endothelial cells treated with palmitic acid and mice fed with a high-fat diet (HFD) were used as the obesity models. The role and mechanism of ASP in endothelial dysfunction were investigated by the means of morphologic, functional, and genetic analysis.
Results
ASP aggravated the endothelial dysfunction induced by either palmitic acid in vitro or an HFD in vivo, characterized as the impairment of endothelium-dependent vasodilation, reduction of nitric oxide levels, elevation of malondialdehyde levels, and inhibition of phosphoinositide 3-kinase–AKT–endothelial nitric oxide synthase signaling. However, adipose conditional knockout of ASP or ASP neutralization significantly alleviated the endothelial dysfunction induced by an HFD. Mechanistically, ASP enhanced mitochondrial fission, and inhibition of the fission through knockdown of dynamin-related protein 1 (a fission-hallmark factor) rescued the endothelial dysfunction and the disturbance to mitochondrial dynamics induced by ASP.
Conclusions
The findings demonstrate that ASP causes and even exacerbates vascular endothelial dysfunction through promoting mitochondrial fission in obesity, suggesting that ASP can act as an early predictive marker of blood vessel dysfunction and become a novel potential therapeutic target for obesity-related cardiovascular diseases.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| oby23656-sup-0001-Supinfo.docxWord 2007 document , 1.9 MB | Appendix S1. Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Romere C, Duerrschmid C, Bournat J, et al. Asprosin, a fasting-induced glucogenic protein hormone. Cell. 2016; 165(3): 566-579.
- 2Li E, Shan H, Chen L, et al. OLFR734 mediates glucose metabolism as a receptor of asprosin. Cell Metab. 2019; 30(2): 319-328.
- 3Miao Y, Qin H, Zhong Y, Huang K, Rao C. Novel adipokine asprosin modulates browning and adipogenesis in white adipose tissue. J Endocrinol. 2021; 249(2): 83-93.
- 4Corica D, Aversa T, Currò M, et al. Asprosin serum levels and glucose homeostasis in children with obesity. Cytokine. 2021; 142:155477.
- 5Wang Y, Qu H, Xiong X, et al. Plasma asprosin concentrations are increased in individuals with glucose dysregulation and correlated with insulin resistance and first-phase insulin secretion. Mediators Inflamm. 2018; 2018: 9471583. doi:10.1155/2018/9471583.
- 6Corica D, Pepe G, Aversa T, et al. Meal-related asprosin serum levels are affected by insulin resistance and impaired fasting glucose in children with obesity. Front Endocrinol (Lausanne). 2022; 12:805700. doi:10.3389/fendo.2021.805700
- 7Long W, Xie X, Du C, et al. Decreased circulating levels of asprosin in obese children. Horm Res Paediatr. 2019; 91(4): 271-277.
- 8Ugur K, Aydin S. Saliva and blood asprosin hormone concentration associated with obesity. Int J Endocrinol. 2019; 2019: 2521096. doi:10.1155/2019/2521096
- 9Zhang X, Jiang H, Ma X, Wu H. Increased serum level and impaired response to glucose fluctuation of asprosin is associated with type 2 diabetes mellitus. J Diabetes Investig. 2020; 11(2): 349-355.
- 10Zhang L, Chen C, Zhou N, Fu Y, Cheng X. Circulating asprosin concentrations are increased in type 2 diabetes mellitus and independently associated with fasting glucose and triglyceride. Clin Chim Acta. 2019; 489: 183-188.
- 11Eckel RH, Bornfeldt KE, Goldberg IJ. Cardiovascular disease in diabetes, beyond glucose. Cell Metab. 2021; 33(8): 1519-1545.
- 12Beverly JK, Budoff MJ. Atherosclerosis: pathophysiology of insulin resistance, hyperglycemia, hyperlipidemia, and inflammation. J Diabetes. 2020; 12(2): 102-104.
- 13Wen MS, Wang CY, Yeh JK, et al. The role of asprosin in patients with dilated cardiomyopathy. BMC Cardiovasc Disord. 2020; 20(1): 402. doi:10.1186/s12872-020-01680-1
- 14Moradi N, Fouani FZ, Vatannejad A, Bakhti Arani A, Shahrzad S, Fadaei R. Serum levels of asprosin in patients diagnosed with coronary artery disease (CAD): a case-control study. Lipids Health Dis. 2021; 20(1): 88. doi:10.1186/s12944-021-01514-9
- 15You M, Liu Y, Wang B, et al. Asprosin induces vascular endothelial-to-mesenchymal transition in diabetic lower extremity peripheral artery disease. Cardiovasc Diabetol. 2022; 21(1): 25. doi:10.1186/s12933-022-01457-0
- 16Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 2020; 15: 235-259.
- 17Li JC, Velagic A, Qin CX, et al. Diabetes attenuates the contribution of endogenous nitric oxide but not nitroxyl to endothelium dependent relaxation of rat carotid arteries. Front Pharmacol. 2021; 11:585740. doi:10.3389/fphar.2020.585740
- 18Razuvaev A, Lund K, Roy J, Hedin U, Caidahl K. Noninvasive real-time imaging of intima thickness after rat carotid artery balloon injury using ultrasound biomicroscopy. Atherosclerosis. 2008; 199(2): 310-316.
- 19Wu J, Zhang H, Zheng H, Jiang Y. Hepatic inflammation scores correlate with common carotid intima-media thickness in rats with NAFLD induced by a high-fat diet. BMC Vet Res. 2014; 10: 162. doi:10.1186/1746-6148-10-162
- 20Tian H, Suo N, Li F, Yang CL, Qiong X. An effective method of isolating endothelial cells from intact rat aorta. Cell Biochem Biophys. 2014; 70(1): 423-427.
- 21Westrate LM, Drocco JA, Martin KR, Hlavacek WS, MacKeigan JP. Mitochondrial morphological features are associated with fission and fusion events. PLoS One. 2014; 9(4):e95265. doi:10.1371/journal.pone.0095265
- 22Chaudhry A, Shi R, Luciani DS. A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic β-cells. Am J Physiol Endocrinol Metab. 2020; 318(2): E87-E101.
- 23Piché ME, Tchernof A, Després JP. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ Res. 2020; 126(11): 1477-1500.
- 24Engin A. Endothelial dysfunction in obesity. Adv Exp Med Biol. 2017; 960: 345-379.
- 25Atawia RT, Bunch KL, Toque HA, Caldwell RB, Caldwell RW. Mechanisms of obesity-induced metabolic and vascular dysfunctions. Front Biosci (Landmark Ed). 2019; 24(5): 890-934.
- 26Matarese G, Mantzoros C, La Cava A. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis. Curr Pharm Des. 2007; 13(36): 3676-3680.
- 27Jamaluddin MS, Weakley SM, Yao Q, Chen C. Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol. 2012; 165(3): 622-632.
- 28Katsiki N, Mantzoros C, Mikhailidis DP. Adiponectin, lipids and atherosclerosis. Curr Opin Lipidol. 2017; 28(4): 347-354.
- 29Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American college of cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2017; 135(17): 726-779.
- 30Peng W, Cai G, Xia Y, et al. Mitochondrial dysfunction in atherosclerosis. DNA Cell Biol. 2019; 38(7): 597-606.
- 31Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014; 94(3): 909-950.
- 32López-Armada MJ, Riveiro-Naveira RR, Vaamonde-García C, Valcárcel-Ares MN. Mitochondrial dysfunction and the inflammatory response. Mitochondrion. 2013; 13(2): 106-118.
- 33Tang X, Luo YX, Chen HZ, Liu DP. Mitochondria, endothelial cell function, and vascular diseases. Front Physiol. 2014; 5: 175. doi:10.3389/fphys.2014.00175
- 34Lee T, Yun S, Jeong JH, Jung TW, et al. Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK-mediated inflammation. Mol Cell Endocrinol. 2019; 486: 96-104.
- 35Beck JT, Ismail A, Tolomeo C. Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. Cancer Treat Rev. 2014; 40(8): 980-989.
- 36Mohamed R, Shajimoon A, Afroz R, et al. Akt acts as a switch for GPCR transactivation of the TGF-β receptor type 1. FEBS J. 2022; 289(9): 2642-2656.
- 37Tao A, Xu X, Kvietys P, Kao R, Martin C, Rui T. Experimental diabetes mellitus exacerbates ischemia/reperfusion-induced myocardial injury by promoting mitochondrial fission: role of down-regulation of myocardial Sirt1 and subsequent Akt/Drp1 interaction. Int J Biochem Cell Biol. 2018; 105: 94-103.
