Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis

DOI Web Site 参考文献44件 オープンアクセス
  • Kyoungmin Park
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Qian Li
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Matthew D. Lynes
    Research Division, Joslin Diabetes Center (K.P., Q.L., M.D.L., H.Y., T.S., R.S.-L., Q.L., J.F., A.C., H.P., I.-H.W., M.G.Y., H.S., Y.-H.T., G.L.K.), Harvard Medical School, Boston, MA.
  • Hisashi Yokomizo
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Ernesto Maddaloni
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Takanori Shinjo
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Ronald St-Louis
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Qin Li
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Sayaka Katagiri
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Jialin Fu
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Allen Clermont
    Research Division, Joslin Diabetes Center (K.P., Q.L., M.D.L., H.Y., T.S., R.S.-L., Q.L., J.F., A.C., H.P., I.-H.W., M.G.Y., H.S., Y.-H.T., G.L.K.), Harvard Medical School, Boston, MA.
  • Hyunseok Park
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • I-Hsien Wu
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Marc Gregory Yu
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Hetal Shah
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.
  • Yu-Hua Tseng
    Research Division, Joslin Diabetes Center (K.P., Q.L., M.D.L., H.Y., T.S., R.S.-L., Q.L., J.F., A.C., H.P., I.-H.W., M.G.Y., H.S., Y.-H.T., G.L.K.), Harvard Medical School, Boston, MA.
  • George L. King
    Dianne Nunnally Hoppes Laboratory (K.P., Q.L., H.Y., E.M., T.S., R.S.L., Q.L., S.K., J.F., H.P., I.-H.W., M.G.Y., H.S., G.L.K.), Harvard Medical School, Boston, MA.

抄録

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> Studies used various endothelial transgenic and deletion mutant <jats:italic>ApoE</jats:italic> <jats:sup>−/−</jats:sup> mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Enhancing insulin’s actions on endothelial cells and NO production in <jats:italic>ECIRS1</jats:italic> transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester ( <jats:sub>L</jats:sub> -NAME), an inhibitor of eNOS, in <jats:italic>ECIRS1</jats:italic> mice and <jats:italic>eNOSKO</jats:italic> mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from <jats:italic>ECIRS1</jats:italic> mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in <jats:italic>ApoE</jats:italic> <jats:sup>−</jats:sup> <jats:sup>/−</jats:sup> mice. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.</jats:p> </jats:sec>

収録刊行物

  • Circulation Research

    Circulation Research 131 (2), 168-183, 2022-07-08

    Ovid Technologies (Wolters Kluwer Health)

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