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Clinical Research in Cardiology
Published in: Clinical Research in Cardiology 11/2016

01-11-2016 | Original Paper

Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis

Authors: Ioannis Drosos, Georgios Chalikias, Maria Pavlaki, Dimitra Kareli, Grigorios Epitropou, Georgios Bougioukas, Dimitrios Mikroulis, Fotios Konstantinou, Alexandra Giatromanolaki, Konstantinos Ritis, Thomas Münzel, Dimitrios Tziakas, Stavros Konstantinides, Katrin Schäfer

Published in: Clinical Research in Cardiology | Issue 11/2016

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Abstract

Aim

The factors mediating the paracrine effects of perivascular adipose tissue (PVAT) in atherosclerosis are largely unknown. The adipokine leptin has been implicated in the increased cardiovascular risk in obesity and may locally promote neointima formation independently of circulating leptin levels. In patients with established coronary artery disease, we examined the expression of leptin as well as of its possible inducers in ‘cardiac’ PVAT surrounding the aortic root and coronary arteries (C-PVAT), and compared it to the PVAT surrounding the internal mammary artery (IMA-PVAT), a vessel resistant to atherosclerosis.

Methods and results

Tissue specimens collected from male patients undergoing coronary artery bypass surgery were processed for real-time PCR, ELISA, in situ hybridization, and immunohistochemistry analysis. Leptin protein expression was elevated in C-PVAT compared to IMA-PVAT, independent of serum leptin levels. Compared to IMA-PVAT, C-PVAT exhibited more pronounced angiogenesis and inflammation, as indicated by significantly higher numbers of PECAM1-positive vessels and CD68-positive macrophages, and was characterized by a greater extent of fibrosis and hypoxia. Increased expression of hypoxia-inducible factor-1α and Fos-like antigen (FOSL)2, factors known to enhance leptin gene transcription, was observed in C-PVAT. As a proof of concept, exposure of human adipocytes to chemical hypoxia resulted in significantly increased FOSL2 and leptin mRNA levels.

Conclusions

A higher degree of local tissue hypoxia and up-regulation of leptin expression in the perivascular adipose tissue, along with increased vascularization, inflammation, and fibrosis, may contribute to the increased atherosclerotic plaque burden in the coronary arteries compared to the IMA.
Appendix
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Literature
1.
Gelber RP, Gaziano JM, Orav EJ, Manson JE, Buring JE, Kurth T (2008) Measures of obesity and cardiovascular risk among men and women. J Am Coll Cardiol 52:605–615CrossRefPubMedPubMedCentral
2.
Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB (2008) Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation 117:1658–1667CrossRefPubMed
3.
Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW (2004) Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145:2273–2282CrossRefPubMed
4.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808CrossRefPubMedPubMedCentral
5.
Fitzgibbons TP, Czech MP (2014) Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc 3:e000582CrossRefPubMedPubMedCentral
6.
Greif M, Becker A, von Ziegler F, Lebherz C, Lehrke M, Broedl UC, Tittus J, Parhofer K, Becker C, Reiser M, Knez A, Leber AW (2009) Pericardial adipose tissue determined by dual source CT is a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol 29:781–786CrossRefPubMed
7.
Mahabadi AA, Reinsch N, Lehmann N, Altenbernd J, Kalsch H, Seibel RM, Erbel R, Mohlenkamp S (2010) Association of pericoronary fat volume with atherosclerotic plaque burden in the underlying coronary artery: a segment analysis. Atherosclerosis 211:195–199CrossRefPubMed
8.
Greif M, von Ziegler F, Wakili R, Tittus J, Becker C, Helbig S, Laubender RP, Schwarz W, D’Anastasi M, Schenzle J, Leber AW, Becker A (2013) Increased pericardial adipose tissue is correlated with atrial fibrillation and left atrial dilatation. Clin Res Cardiol 102:555–562CrossRefPubMed
9.
Otsuka F, Yahagi K, Sakakura K, Virmani R (2013) Why is the mammary artery so special and what protects it from atherosclerosis? Ann Cardiothorac Surg 2:519–526PubMedPubMedCentral
10.
Malinowski M, Deja MA, Janusiewicz P, Golba KS, Roleder T, Wos S (2013) Mechanisms of vasodilatatory effect of perivascular tissue of human internal thoracic artery. J Physiol Pharmacol 64:309–316PubMed
11.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295CrossRefPubMed
12.
Schäfer K, Konstantinides SV (2011) Update on the cardiovascular risk in obesity: endocrine and paracrine role of the adipose tissue. Hellenic J Cardiol 52:327–336PubMed
13.
Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N (2001) Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 104:3052–3056CrossRefPubMed
14.
Wolk R, Berger P, Lennon RJ, Brilakis ES, Johnson BD, Somers VK (2004) Plasma leptin and prognosis in patients with established coronary atherosclerosis. J Am Coll Cardiol 44:1819–1824CrossRefPubMed
15.
Ciccone M, Vettor R, Pannacciulli N, Minenna A, Bellacicco M, Rizzon P, Giorgino R, De Pergola G (2001) Plasma leptin is independently associated with the intima-media thickness of the common carotid artery. Int J Obes Relat Metab Disord 25:805–810CrossRefPubMed
16.
Qasim A, Mehta NN, Tadesse MG, Wolfe ML, Rhodes T, Girman C, Reilly MP (2008) Adipokines, insulin resistance, and coronary artery calcification. J Am Coll Cardiol 52:231–236CrossRefPubMedPubMedCentral
17.
Weissgerber A, Scholz M, Teren A, Sandri M, Teupser D, Gielen S, Thiery J, Schuler G, Beutner F (2016) The value of noncoronary atherosclerosis for identifying coronary artery disease: results of the Leipzig LIFE Heart Study. Clin Res Cardiol 105:172–181CrossRefPubMed
18.
Schroeter MR, Schneiderman J, Schumann B, Glückermann R, Grimmas P, Buchwald AB, Tirilomis T, Schöndube FA, Konstantinides SV, Schäfer K (2007) Expression of the leptin receptor in different types of vascular lesions. Histochem Cell Biol 128:323–333CrossRefPubMed
19.
Konstantinides S, Schäfer K, Koschnick S, Loskutoff DJ (2001) Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 108:1533–1540CrossRefPubMedPubMedCentral
20.
Schäfer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, Konstantinides S (2004) Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 24:112–117CrossRefPubMed
21.
Bodary PF, Gu S, Shen Y, Hasty AH, Buckler JM, Eitzman DT (2005) Recombinant leptin promotes atherosclerosis and thrombosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:e119–e122CrossRefPubMed
22.
Schroeter MR, Eschholz N, Herzberg S, Jerchel I, Leifheit-Nestler M, Czepluch FS, Chalikias G, Konstantinides S, Schäfer K (2013) Leptin-dependent and leptin-independent paracrine effects of perivascular adipose tissue on neointima formation. Arterioscler Thromb Vasc Biol 33:980–987CrossRefPubMed
23.
Cheng KH, Chu CS, Lee KT, Lin TH, Hsieh CC, Chiu CC, Voon WC, Sheu SH, Lai WT (2008) Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int J Obes (Lond) 32:268–274CrossRef
24.
Regitz-Zagrosek V, Lehmkuhl E, Weickert MO (2006) Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin Res Cardiol 95:136–147CrossRefPubMed
25.
Chechi K, Gelinas Y, Mathieu P, Deshaies Y, Richard D (2012) Validation of reference genes for the relative quantification of gene expression in human epicardial adipose tissue. PLoS One 7:e32265CrossRefPubMedPubMedCentral
26.
Neville MJ, Collins JM, Gloyn AL, McCarthy MI, Karpe F (2011) Comprehensive human adipose tissue mRNA and microRNA endogenous control selection for quantitative real-time-PCR normalization. Obesity (Silver Spring) 19:888–892CrossRef
27.
Schneiderman J, Schäfer K, Kolodgie FD, Savion N, Kotev-Emeth S, Dardik R, Simon AJ, Halak M, Pariente C, Engelberg I, Konstantinides S, Virmani R (2012) Leptin locally synthesized in carotid atherosclerotic plaques could be associated with lesion instability and cerebral emboli. J Am Heart Assoc 1:e001727CrossRefPubMedPubMedCentral
28.
Wrann CD, Eguchi J, Bozec A, Xu Z, Mikkelsen T, Gimble J, Nave H, Wagner EF, Ong SE, Rosen ED (2012) FOSL2 promotes leptin gene expression in human and mouse adipocytes. J Clin Invest 122:1010–1021CrossRefPubMedPubMedCentral
29.
Heida NM, Leifheit-Nestler M, Schroeter MR, Müller JP, Cheng IF, Henkel S, Limbourg A, Limbourg FP, Alves F, Quigley JP, Ruggeri ZM, Hasenfuss G, Konstantinides S, Schäfer K (2010) Leptin enhances the potency of circulating angiogenic cells via src kinase and integrin alphaVbeta5: implications for angiogenesis in human obesity. Arterioscler Thromb Vasc Biol 30:200–206CrossRefPubMed
30.
Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR (1998) Biological action of leptin as an angiogenic factor. Science 281:1683–1686CrossRefPubMed
31.
Fernandez-Riejos P, Najib S, Santos-Alvarez J, Martin-Romero C, Perez-Perez A, Gonzalez-Yanes C, Sanchez-Margalet V (2010) Role of leptin in the activation of immune cells. Mediators Inflamm 2010:568343CrossRefPubMedPubMedCentral
32.
Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J (2003) Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 100:4736–4741CrossRefPubMedPubMedCentral
33.
Keophiphath M, Achard V, Henegar C, Rouault C, Clement K, Lacasa D (2009) Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. Mol Endocrinol 23:11–24CrossRefPubMed
34.
Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083PubMed
35.
Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL (2009) Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension 54:1384–1392CrossRefPubMed
36.
Xu X, Liu C, Xu Z, Tzan K, Wang A, Rajagopalan S, Sun Q (2012) Altered adipocyte progenitor population and adipose-related gene profile in adipose tissue by long-term high-fat diet in mice. Life Sci 90:1001–1009CrossRefPubMedPubMedCentral
37.
Padilla J, Jenkins NT, Vieira-Potter VJ, Laughlin MH (2013) Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. Am J Physiol Regul Integr Comp Physiol 304:R543–R552CrossRefPubMedPubMedCentral
38.
Chatterjee TK, Aronow BJ, Tong WS, Manka D, Tang Y, Bogdanov VY, Unruh D, Blomkalns AL, Piegore MG Jr, Weintraub DS, Rudich SM, Kuhel DG, Hui DY, Weintraub NL (2013) Human coronary artery perivascular adipocytes overexpress genes responsible for regulating vascular morphology, inflammation, and hemostasis. Physiol Genomics 45:697–709CrossRefPubMedPubMedCentral
39.
Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, Sarov-Blat L, O’Brien S, Keiper EA, Johnson AG, Martin J, Goldstein BJ, Shi Y (2003) Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108:2460–2466CrossRefPubMed
40.
de Vos AM, Prokop M, Roos CJ, Meijs MF, van der Schouw YT, Rutten A, Gorter PM, Cramer MJ, Doevendans PA, Rensing BJ, Bartelink ML, Velthuis BK, Mosterd A, Bots ML (2008) Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. Eur Heart J 29:777–783CrossRefPubMed
41.
Park JS, Choi BJ, Choi SY, Yoon MH, Hwang GS, Tahk SJ, Shin JH (2013) Echocardiographically measured epicardial fat predicts restenosis after coronary stenting. Scand Cardiovasc J 47:297–302CrossRefPubMed
42.
Ohman MK, Luo W, Wang H, Guo C, Abdallah W, Russo HM, Eitzman DT (2011) Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice. Atherosclerosis 219:33–39CrossRefPubMedPubMedCentral
43.
Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, Saito Y, Nagai R, Sata M (2009) Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res 105:906–911CrossRefPubMed
44.
Takaoka M, Suzuki H, Shioda S, Sekikawa K, Saito Y, Nagai R, Sata M (2010) Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler Thromb Vasc Biol 30:1576–1582CrossRefPubMed
45.
Manka D, Chatterjee TK, Stoll LL, Basford JE, Konaniah ES, Srinivasan R, Bogdanov VY, Tang Y, Blomkalns AL, Hui DY, Weintraub NL (2014) Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte chemoattractant protein-1. Arterioscler Thromb Vasc Biol 34:1723–1730CrossRefPubMedPubMedCentral
46.
Sattar N, Wannamethee G, Sarwar N, Chernova J, Lawlor DA, Kelly A, Wallace AM, Danesh J, Whincup PH (2009) Leptin and coronary heart disease: prospective study and systematic review. J Am Coll Cardiol 53:167–175CrossRefPubMed
47.
Oda A, Taniguchi T, Yokoyama M (2001) Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci 47:141–150PubMed
48.
Rittig K, Dolderer JH, Balletshofer B, Machann J, Schick F, Meile T, Kuper M, Stock UA, Staiger H, Machicao F, Schaller HE, Konigsrainer A, Haring HU, Siegel-Axel DI (2012) The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells. Diabetologia 55:1514–1525CrossRefPubMed
49.
Hollenberg AN, Susulic VS, Madura JP, Zhang B, Moller DE, Tontonoz P, Sarraf P, Spiegelman BM, Lowell BB (1997) Functional antagonism between CCAAT/Enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma on the leptin promoter. J Biol Chem 272:5283–5290CrossRefPubMed
50.
He Y, Chen H, Quon MJ, Reitman M (1995) The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein alpha. J Biol Chem 270:28887–28891CrossRefPubMed
51.
Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J (2002) Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 277:34601–34609CrossRefPubMed
52.
Butler TL, Pennypacker KR (2005) The transcriptional response to hypoxic insult controlled by FRA-2. Gene Expr 12:61–67CrossRefPubMed
53.
Takahashi Y, Satoh M, Tabuchi T, Nakamura M (2012) Prospective, randomized, single-blind comparison of effects of 6 months’ treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease. Heart Vessels 27:337–343CrossRefPubMed
54.
Zeng ZH, Zhang ZH, Luo BH, He WK, Liang LY, He CC, Su CJ (2009) The functional changes of the perivascular adipose tissue in spontaneously hypertensive rats and the effects of atorvastatin therapy. Clin Exp Hypertens 31:355–363CrossRefPubMed
55.
Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, Jeziorska M, Laing I, Yates AP, Pemberton PW, Malik RA, Heagerty AM (2009) Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119:1661–1670CrossRefPubMed
56.
van Hinsbergh VW, Eringa EC, Daemen MJ (2015) Neovascularization of the atherosclerotic plaque: interplay between atherosclerotic lesion, adventitia-derived microvessels and perivascular fat. Curr Opin Lipidol 26:405–411CrossRefPubMed
57.
Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE (2009) Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29:4467–4483CrossRefPubMedPubMedCentral
Metadata
Title
Differences between perivascular adipose tissue surrounding the heart and the internal mammary artery: possible role for the leptin-inflammation-fibrosis-hypoxia axis
Authors
Ioannis Drosos
Georgios Chalikias
Maria Pavlaki
Dimitra Kareli
Grigorios Epitropou
Georgios Bougioukas
Dimitrios Mikroulis
Fotios Konstantinou
Alexandra Giatromanolaki
Konstantinos Ritis
Thomas Münzel
Dimitrios Tziakas
Stavros Konstantinides
Katrin Schäfer
Publication date
01-11-2016
Publisher
Springer Berlin Heidelberg
Published in
Clinical Research in Cardiology / Issue 11/2016
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-016-0996-7

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