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Subepicardial adipose tissue in human coronary atherosclerosis: another neglected phenomenon

      In a recent paper in Atherosclerosis, Scher [
      • Scher A.M.
      Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon.
      ] presented an intriguing viewpoint about one neglected phenomenon: absence of atherosclerosis in intramyocardial coronary arteries. Scher discussed the difference in susceptibility to atherosclerosis between proximal and intramyocardial segments, focusing on myocardial contraction protection against the transfer of circulating LDL and monocytes into the intima. Anatomically, one may speculate that both intramyocardial arteries and tunneled (overbridged by myocardial fibers) epicardial arteries possess, in addition to tunica intima, media, and adventitia, tunica cardiomuscularis. If Scher's viewpoint is a ‘likely’ hypothesis ([
      • Scher A.M.
      Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon.
      ], his Discussion, p. 3), could transplantation of tunica cardiomuscularis protect epicardial coronaries from atherosclerosis? Whatever the mechansim of atherosclerosis resistance of intramyocardial and overbridged coronary arteries, Scher neglected another phenomenon: the potential role of subepicardial adipose tissue (SEAT) in coronary atherosclerosis. This issue is discussed rarely, also by other authors. Another neglected phenomenon? Here we focus on it. The adipose tissue surrounding the most atherosclerosis-prone segment of the coronary artery, that is, the most proximal part of its left anterior descending (LAD) branch, is, in fact, the SEAT. In 1933, Smith and Willius [
      • Marchington J.M.
      • Mattacks C.A.
      • Pond C.M.
      Adipose tissue in the mammalian heart and pericardium: structure, foetal development and biochemical properties.
      ] have pointed out a functional relationship between the SEAT and the LAD coronary artery, and stated that SEAT is ‘not a passive storehouse for fat’. The past 5 years have seen an exponential growth in the understanding of endocrine and paracrine secretory function of adipose tissue [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ,
      • Loskutoff D.J.
      • Fujisawa K.
      • Samad F.
      The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM.
      ,
      • Chaldakov G.N.
      • Fiore M.
      • Ghenev P.I.
      • Stankulov I.S.
      • Aloe L.
      Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue.
      ], in addition to its role in lipid and energy homeostasis. The principle difference between SEAT and adipose tissue elsewhere in the body is its greater capacity for free fatty acid (FFA) release and uptake, thus acting as a local energy supply for the heart and/or as a buffer against toxic levels of FFA [
      • Marchington J.M.
      • Mattacks C.A.
      • Pond C.M.
      Adipose tissue in the mammalian heart and pericardium: structure, foetal development and biochemical properties.
      ]. Neglected for nearly 60 years, the possible involvement of SEAT in atherosclerosis has been, at long last, currently addressed (reviewed in [
      • Chaldakov G.N.
      • Fiore M.
      • Ghenev P.I.
      • Stankulov I.S.
      • Aloe L.
      Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue.
      ]). These findings taken together demonstrate an increase number of both lymphocytes and mast cells, and neovascularization. That is, an inflammatory response-to-injury, originally described by Russell Ross in the intima, may also occur in the ‘atherosclerotic’ SEAT. Probably, SEAT should not be considered an innocent bystander, but a paracrine, SEAT-to-adventitia player in coronary atherosclerosis. One thing appears to be certain: to further elucidate the role of SEAT in atherogenesis, we should no longer, as hitherto, ‘carefully’ cut it from the artery wall, but keep it attached and in place, and subject to thorough examination. One could also see small bundles of cardiomyocytes scattered in SEAT, in human coronary atherosclerosis (our unpublished observations). Could that be, in sense of Scher's viewpoint, a natural compensatory reaction, an attempt of myocardial fibers to overbridge the coronary artery? Another important reason for SEAT to be studied in atherosclerosis is the close association of the coronary vasculogenesis with epicardial development [
      • Hidai H.
      • Bardales R.
      • Goodwin R.
      • Quertermous T.
      • Quetermous E.E.
      Cloning of capsulin, a basic helix–loop–helix factor expressed in progenitor cells of the pericardium and the coronary arteries.
      ,
      • Landerholm T.E.
      • Dong X.R.
      • Lu J.
      • Belaguli N.S.
      • Schwartz R.J.
      • Majesky M.W.
      A role for serum response factor in coronary smooth muscle differentiation from proepicardial cells.
      ], showing that coronary smooth muscle cells (SMC) distinguish themselves ontologically, structurally and functionally as compared with SMC in other great blood vessels. This is implicated in an increased susceptibility of the coronary artery to atherosclerosis [
      • Landerholm T.E.
      • Dong X.R.
      • Lu J.
      • Belaguli N.S.
      • Schwartz R.J.
      • Majesky M.W.
      A role for serum response factor in coronary smooth muscle differentiation from proepicardial cells.
      ]. However, the question arises as to whether SEAT may also contribute to that? Because macrophage colonystimulating factor (MCSF) is a potent adipogenic factor [
      • Levine J.A.
      • Jensen M.D.
      • Eberhardt N.L.
      • O'Brien T.
      Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth.
      ], it is possible for the decreased atherosclerosis found in mice deficient in both MCSF and apolipoprotein E [
      • Smith J.D.
      • Trogan E.
      • Ginsberg M.
      • Grgaux C.
      • Tian J.
      • Miyata M.
      Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E.
      ] to be mediated, at least in part, via a decreased growth of adipose tissue and/or a loss of passage of MCSF's atherogenic signals from the artery-associated adipose tissue into the artery wall. It is also noteworthy that (i) leptin [
      • Kang S.M.
      • Kwon H.M.
      • Hong B.K.
      • et al.
      Expression of leptin receptor (Ob-R) in human atherosclerotic lesions: potential role in intimal neovascularization.
      ] and other adipose tissue-secreted molecules (adipocytokines, adipokines) [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ,
      • Chaldakov G.N.
      • Fiore M.
      • Ghenev P.I.
      • Stankulov I.S.
      • Aloe L.
      Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue.
      ], such as plasminogen activator inhibitor-1 [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ,
      • Loskutoff D.J.
      • Fujisawa K.
      • Samad F.
      The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM.
      ], adiponectin [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ], tissue factor [
      • Loskutoff D.J.
      • Fujisawa K.
      • Samad F.
      The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM.
      ], transforming growth factor-β [
      • Loskutoff D.J.
      • Fujisawa K.
      • Samad F.
      The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM.
      ], and nerve growth factor ([
      • Chaldakov G.N.
      • Properzi F.
      • Ghenev P.I.
      • Fiore M.
      • Stankulov I.S.
      • Aloe L.
      Artery-associated adipose tissue and atherosclerosis: a correlative study of NGF, p75NGF receptor and mast cells in human coronary atherosclerosis.
      ]; also the manuscript submitted to Atherosclerosis), are implicated in atherogenesis, and (ii) lipidsoluble substances may accumulate in SEAT, and hence related to ischemic myocardial events [
      • Strejc P.
      • Gross R.
      • Buchta M.
      Polychlorinated biphenyls in human subepicardial fat.
      ]. We propose a comprehensive evaluation of SEAT-derived adipokines. Besides various adipokines with atherogenic potentials [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ,
      • Loskutoff D.J.
      • Fujisawa K.
      • Samad F.
      The fat mouse. A powerful genetic model to study hemostatic gene expression in obesity/NIDDM.
      ,
      • Chaldakov G.N.
      • Fiore M.
      • Ghenev P.I.
      • Stankulov I.S.
      • Aloe L.
      Atherosclerotic lesions: possible interactive involvement of intima, adventitia and associated adipose tissue.
      ] adipose tissue secretes estrogens [
      • Bulun S.E.
      • Sharda G.
      • Rink J.
      • Sharma S.
      • Simpson E.R.
      Distribution of aromatase P450 transcript and adipose fibroblasts in the human breast.
      ] and adiponectin [
      • Funahashi T.
      • Nakamura T.
      • Shimomura I.
      • et al.
      Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity.
      ], and accumulates carotenoids and tocopherols [
      • Su L.C.
      • Bui M.
      • Kardinaal A.
      • et al.
      Differences between plasma and adipose tissue biomarkers of carotenoids and tocopherols.
      ]; all these molecules may exert an antiatherogenic action. Learning more about the balance between such pro- and antiatherogenic molecules, SEAT may appear to be an important therapeutic target in coronary atherosclerosis.
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