PEDF and PEDF-derived peptide 44mer stimulate cardiac triglyceride degradation via ATGL

Journal of Translational Medicine

Hongyan Dong¹  Zhongming Zhang²  Zhiwei Liu¹  Wei Zhuang¹  Huazhu Cui²  Tengteng Wei²  Meng Wang¹  Hongli Yu¹  Xia Jiang²  Teng Sun²  Hao Zhang² 

[1] Research Facility Center for Morphology, Xuzhou Medical College, Xuzhou 221004, China;Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221006, China

关键词: Triglyceride;    Myocardial infarction;    ATGL;    44mer;    Pigment epithelium-derived factor;   

Others  :  1132843
DOI  :  10.1186/s12967-015-0432-1

 received in 2014-12-29, accepted in 2015-02-10,  发布年份 2015

【 摘 要 】

Background

Pigment epithelium-derived factor (PEDF) is a 50-kDa secreted glycoprotein that is highly expressed in cardiomyocytes. A variety of peptides derived from PEDF exerts diverse physiological activities including anti-angiogenesis, antivasopermeability, and neurotrophic activities. Recent studies demonstrated that segmental functional peptides of PEDF, 44mer peptide (Val78–Thr121), show similar neurotrophic and cytoprotective effect to that of the holoprotein. We found that PEDF can reduce infarct size and protect cardiac function after acute myocardial infarction (AMI). However, the effects of PEDF on cardiac triglyceride (TG) accumulation after AMI remain unknown. The present study was performed to demonstrate the influence of PEDF and its functional peptides 44mer on TG degradation in AMI.

Methods

The left ascending coronary artery (LAD) was ligated to induce AMI. PEDF-small interfering RNA (siRNA)-lentivirus (PEDF-RNAi-LV) or PEDF-LV was delivered to the ischemic myocardium in order to knock down or overexpress PEDF, respectively. Oil Red O staining and a TG assay kit were used to analyze the TG content in cardiomyocytes and infarcted areas.

Results

The TG content significantly decreased in the PEDF-overexpressing heart compared to the sham group (P < 0.05). Both rPEDF and 44mer administration stimulate the TG degradation in cultured cardiomyocytes (P < 0.05). Adipose triglyceride lipase (ATGL)-specific inhibitor, atglistatin, attenuated the PEDF or 44mer-induced TG lipolysis activation of cardiomyocytes at 10 μmol/L. The effects of PEDF and 44mer on myocardial TG degradation were also abolished when ATGL was downregulated.

Conclusions

We conclude that PEDF and 44mer promote TG degradation in cardiomyocytes after AMI via ATGL. The substitution of PEDF and 44mer may be a novel therapeutic strategy for cardiac TG accumulation after AMI.

【 授权许可】

   
2015 Zhang et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Huss JM, Levy FH, Kelly DP: Hypoxia inhibits the peroxisome proliferator-activated receptor alpha/retinoid X receptor gene regulatory pathway in cardiac myocytes: a mechanism for O2-dependent modulation of mitochondrial fatty acid oxidation. J Biol Chem 2001, 276:27605-27612.
• [2]van Herpen NA, Schrauwen-Hinderling VB: Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol Behav 2008, 94:231-241.
• [3]Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al.: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 2000, 97:1784-1789.
• [4]Becerra SP, Sagasti A, Spinella P, Notario V: Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J Biol Chem 1995, 270:25992-25999.
• [5]Filleur S, Nelius T, de Riese W, Kennedy RC: Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem 2009, 106:769-775.
• [6]Wang Y, Subramanian P, Shen D, Tuo J, Becerra SP, Chan CC: Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. ASN Neuro 2013, 5:e00126.
• [7]Wang P, Smit E, Brouwers MC, Goossens GH, van der Kallen CJ, van Greevenbroek MM, et al.: Plasma pigment epithelium-derived factor is positively associated with obesity in Caucasian subjects, in particular with the visceral fat depot. Eur J Endocrinol 2008, 159:713-718.
• [8]Yamagishi S, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K, et al.: Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab 2006, 91:2447-2450.
• [9]Jenkins A, Zhang SX, Gosmanova A, Aston C, Dashti A, Baker MZ, et al.: Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients. Diabetes Res Clin Pract 2008, 82:e5-7.
• [10]Borg ML, Andrews ZB, Duh EJ, Zechner R, Meikle PJ, Watt MJ: Pigment epithelium-derived factor regulates lipid metabolism via adipose triglyceride lipase. Diabetes 2011, 60:1458-1466.
• [11]Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, et al.: Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem 2006, 281:38022-38037.
• [12]Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, et al.: Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004, 306:1383-1386.
• [13]Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de Weijer T, et al.: ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 2011, 17:1076-1085.
• [14]Kienesberger PC, Pulinilkunnil T, Sung MM, Nagendran J, Haemmerle G, Kershaw EE, et al.: Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction. Mol Cell Biol 2012, 32:740-750.
• [15]Kawaguchi T, Yamagishi SI, Sata M: Structure-function relationships of PEDF. Curr Mol Med 2010, 10:302-311.
• [16]Gao X, Zhang H, Zhuang W, Yuan G, Sun T, Jiang X, et al.: PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia-induced apoptosis and necroptosis via anti-oxidative effect. Sci Rep 2014, 4:5637.
• [17]Lei X, Feng S, Chen L, Shi H, Zhang Z, Dong H: Effect of PEDF on cardiac function and its mechanisms in rat ischemic heart. Acta Academiae Medicinae Xuzhou 2013, 33:355-359.
• [18]Nishimura K, Hiramatsu K, Monir MM, Takemoto C, Watanabe T: Ultrastructural study on colocalization of glucagon-like peptide (GLP)-1 with GLP-2 in chicken intestinal L-cells. J Vet Med Sci 2013, 75:1335-1339.
• [19]Baba H, Yonemitsu Y, Nakano T, Onimaru M, Miyazaki M, Ikeda Y, et al.: Cytoplasmic expression and extracellular deposition of an antiangiogenic factor, pigment epithelium-derived factor, in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2005, 25:1938-1944.
• [20]Taegtmeyer H: Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol 1994, 19:59-113.
• [21]Perman JC, Bostrom P, Lindbom M, Lidberg U, StAhlman M, Hagg D, et al.: The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest 2011, 121:2625-2640.
• [22]Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC: Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010, 90:207-258.
• [23]Bilheimer DW, Buja LM, Parkey RW, Bonte FJ, Willerson JT: Fatty acid accumulation and abnormal lipid deposition in peripheral and border zones of experimental myocardial infarcts. J Nucl Med 1978, 19:276-283.
• [24]Rychli K, Kaun C, Hohensinner PJ, Dorfner AJ, Pfaffenberger S, Niessner A, et al.: The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts. J Cell Mol Med 2010, 14:198-205.
• [25]Tombran-Tink J, Chader GG, Johnson LV: PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 1991, 53:411-414.
• [26]Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, et al.: Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 2002, 8:349-357.
• [27]Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS: Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 2004, 279:47066-47075.
• [28]Fischer J, Lefevre C, Morava E, Mussini JM, Laforet P, Negre-Salvayre A, et al.: The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 2007, 39:28-30.
• [29]Schrammel A, Mussbacher M, Winkler S, Haemmerle G, Stessel H, Wolkart G, et al.: Cardiac oxidative stress in a mouse model of neutral lipid storage disease. Biochim Biophys Acta 1831, 2013:1600-1608.
• [30]Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, et al.: Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006, 312:734-737.
• [31]Chung C, Doll JA, Gattu AK, Shugrue C, Cornwell M, Fitchev P, et al.: Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol 2008, 48:471-478.
• [32]Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, et al.: Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab 2006, 3:309-319.
• [33]Ong KT, Mashek MT, Bu SY, Mashek DG: Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation. FASEB J 2013, 27:313-321.