Inhibition of FABP4 attenuates cardiac fibrosis through inhibition of NLRP3 inflammasome activation

Document Type : Original Article


Department of Cardiology, Shanghai University of Medicine & Health Sciences affiliated Zhoupu Hospital, Shanghai 201318, China


Objective(s): Cardiac fibrosis is a key biological process of cardiac remodeling and heart failure. Fatty acid-binding protein 4 (FABP4) is a lipid-binding protein that can regulate glucose and lipid homeostasis, and its expression was elevated in heart failure. However, whether FABP4 is involved in cardiac fibrosis remains unknown. 
Materials and Methods: The cardiac fibrosis model was established in male C57BL/6 mice with subcutaneously infused angiotensin II (Ang-II) (2.8 mg/kg/day) for 4 weeks. DMSO or FABP4 inhibitor BMS309403 (50 mg/kg/day) was intraperitoneally injected for 4 weeks. Ang II-infused mice, FABP4 inhibitor (BMS309403) injected mice, and ventricular tissue were used for morphological studies, and histological and biochemical analyses (FABP4 protein composition and expression).
Results: Ang II infusion increased FABP4 mRNA and protein expression in the mouse ventricular tissue. After treatment with FABP4 inhibitor BMS309403 for 4 weeks, mice showed improved cardiac structure and function as detected by echocardiography. BMS309403 suppressed cardiac and systemic inflammatory response, reduced collagen deposition, and mRNA expression of collagen type I (COL1A1) and collagen type III (COL3A1) in Ang II-infused mice. BMS309403 also reduced the number of α-smooth muscle actin (α-SMA)+cells and decreased the mRNA expression of α-SMA, matrix metalloproteinases-2 (MMP-2), MMP-9, and transforming growth factor-β (TGF‑β) in ventricular tissue.
Conclusion: The inhibitory effect of BMS309403 on cardiac fibrosis might be associated with inhibition of NLRP3 inflammasome activation, which Ang II activated. Thus, our data speculated that inhibition of FABP4 could significantly induce cardiac fibrosis.


1. Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest 2007; 117: 568-575.
2.  Lyon RC, Zanella F, Omens JH, and Sheikh F. Mechanotransduction in cardiac hypertrophy and failure. Circ Res 2015; 116:1462-1476.
3. Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med 2019; 65: 70-99.
4. Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, et al. The processes and mechanisms of cardiac and pulmonary fibrosis. Front Physiol 2017; 8: 777.
5. Chen J, Chen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature 2018; 564: 71-76.
6. Duewell P, Kono H, Rayner KJ, Sirois CM,  Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357-1361.
7. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016; 16: 407-420.
8. Abderrazak A, Syrovets T, Couchie D, Hardi KE, Friguet B, Simmet T, et al. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol 2015; 4: 296-307.
9. Lamkanfi M and Dixit VM. Infammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 2012; 28: 137-161.
10. Spiegelman BM, Frank M, Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem 1983; 258:10083-10089.
11. Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM. Adipocyte P2 gene: developmental expression and homology of 5’-flanking sequences among fat cell specific genes. Proc Natl Acad Sci 1986; 83:3786-3790.
12. Simón I, Escoté X, Vilarrasa N, Gómez J, Fernández-Real JM, Megía A, et al. Adipocyte fatty acid-binding protein as a determinant of insulin sensitivity in morbid-obese women. Obesity 2009; 17:1124-1128.
13. Tso AWK, Xu A, Shan PC, Wat NMS, Wang Y, Fong CHY, et al. Serum adipocyte fatty acid-binding protein as a new biomarker predicting the development of Type 2 diabetes. Diabetes Care 2007; 30:2667-2672.
14. Lorenzo-Almorós A, Hang T, Peiró C, Soriano-Guillén L, Egido J, Tuñón J, et al. Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases. Cardiovasc Diabetol 2019; 18: 140.
15. Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006; 52: 405-413. 
16. Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clin Med Insights Cardiol 2014; 2014:23-33.
17. Jin J, Peng DQ, Yuan SG, Zhao SP, Ning XH, Wang SH, et al. Serum adipocyte fatty acid binding proteins and adiponectin in patients with coronary artery disease: the significance of A-FABP/adiponectin ratio. Clinica Chimica Acta 2010; 411:1761-1765.
18. Liu M, Zhou M, Bao Y, Xu Z, Li H, Zhang H, et al. Circulating adipocyte fatty acid-binding protein levels are independently associated with heart failure. Clin Sci 2013; 124 : 115-122.
19. Feng Y, Guo F, Xia Z, Liu J, Mai H, Liang Y, et al. Inhibition of fatty acid‐binding protein 4 attenuated kidney fibrosis by mediating macrophage‐to‐myofibroblast transition. Front Immunol 2020; 11: 566535.
20. Kurokawa J, and Abriel H. Neurohormonal regulation of cardiac ion channels in chronic heart failure. J Cardiovasc Pharmacol 2009; 54: 98-105.
21. Nguyen TP, Qu Z, Weiss JN. Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J Mol Cell Cardiol 2014; 70: 83-91.
22. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 2014; 71:549-574.
23. Hinderer S, Schenke-Layland K. Cardiac fibrosis - a short review of causes and therapeutic strategies. Adv Drug Deliv Rev 2019; 146:77-82.
24. Moore-Morris T, Guimaraes-Camboa N, Yutzey KE, Puceat M, Evans SM. Cardiac fibroblasts: From development to heart failure. J Mol Med 2015; 93:823-830.
25. Daccarett M, Badger TJ, Akoum N, Burgon NS, Mahnkopf C, Vergara G, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011; 57: 831-838.
26. Akoum N, McGann C, Vergara G, Badger T, Ranjan R, Mahnkopf C, et al. Atrial fibrosis quantified using late gadolinium enhancement MRI is associated with sinus node dysfunction requiring pacemaker implant. J Cardiovasc Electrophysiol 2012: 23: 44-50.
27. Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 2001; 7: 699-705.
28. Huang CL, Wu YW, Wu CC, Lin L, Wu YC, Hsu PY, et al. Association between serum adipocyte fatty-acid binding protein concentrations, left ventricular function and myocardial perfusion abnormalities in patients with coronary artery disease. Cardiovasc Diabetol 2013; 12: 105.
29. Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 2007;447: 959-965.
30. Yue Y, Meng K, Pu Y and Zhang X. Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract 2017; 133: 124-130.
31. Heger J, Schulz R and Euler G. Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure. Br J Pharmacol 2016; 173: 3-14.
32. Franchi L, Eigenbrod T, Muñoz-Planillo R, and Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 2009; 10: 241-247.
33. He Y, Hara H, and Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci 2016; 41: 1012-1021.
34. Steen KA, Xu H, and Bernlohr DA. FABP4/aP2 regulates macrophage redox signaling and inflammasome activation via control of UCP2. Mol Cell Biol 2017; 37: e00282.
35. Gao Q, Jiang Y, Dai S, Wang B, Gao F, Guo C, et al. Interleukin 17A exacerbates atherosclerosis by promoting fatty acid-binding protein 4-mediated ER stress in macrophages. Circ Res 2012; 112: 87.