TY - JOUR
T1 - Hematopoietic deficiency of the long noncoding RNA malat1 promotes atherosclerosis and plaque inflammation
AU - Cremer, Sebastian
AU - Michalik, Katharina M.
AU - Fischer, Ariane
AU - Pfisterer, Larissa
AU - Jaé, Nicolas
AU - Winter, Carla
AU - Boon, Reinier A.
AU - Muhly-Reinholz, Marion
AU - John, David
AU - Uchida, Shizuka
AU - Weber, Christian
AU - Poller, Wolfgang
AU - Günther, Stefan
AU - Braun, Thomas
AU - Li, Daniel Y.
AU - Maegdefessel, Lars
AU - Perisic Matic, Ljubica
AU - Hedin, Ulf
AU - Soehnlein, Oliver
AU - Zeiher, Andreas
AU - Dimmeler, Stefanie
PY - 2019/3/5
Y1 - 2019/3/5
N2 - Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-Associated lung adenocarcinoma transcript 1) on atherosclerosis was examined. Methods: The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe-/-) MALAT1-deficient (Malat1-/-) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques. Results: Apoe-/- Malat1-/- mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45+ cells compared with Apoe-/- Malat1+/+ control mice. Bone marrow transplantation of Apoe-/- Malat1-/- bone marrow cells in Apoe-/- Malat1+/+ mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1-/- mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1-/- mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis. Conclusions: Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1-/- mice were mainly caused by enhanced accumulation of hematopoietic cells.
AB - Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long noncoding RNAs (lncRNAs). lncRNAs exhibit multiple functions, including the epigenetic control of gene expression. In this study, the effect of the lncRNA MALAT1 (metastasis-Associated lung adenocarcinoma transcript 1) on atherosclerosis was examined. Methods: The effect of MALAT1 on atherosclerosis was determined in apolipoprotein E-deficient (Apoe-/-) MALAT1-deficient (Malat1-/-) mice that were fed with a high-fat diet and by studying the regulation of MALAT1 in human plaques. Results: Apoe-/- Malat1-/- mice that were fed a high-fat diet showed increased plaque size and infiltration of inflammatory CD45+ cells compared with Apoe-/- Malat1+/+ control mice. Bone marrow transplantation of Apoe-/- Malat1-/- bone marrow cells in Apoe-/- Malat1+/+ mice enhanced atherosclerotic lesion formation, which suggests that hematopoietic cells mediate the proatherosclerotic phenotype. Indeed, bone marrow cells isolated from Malat1-/- mice showed increased adhesion to endothelial cells and elevated levels of proinflammatory mediators. Moreover, myeloid cells of Malat1-/- mice displayed enhanced adhesion to atherosclerotic arteries in vivo. The anti-inflammatory effects of MALAT1 were attributed in part to reduction of the microRNA miR-503. MALAT1 expression was further significantly decreased in human plaques compared with normal arteries and was lower in symptomatic versus asymptomatic patients. Lower levels of MALAT1 in human plaques were associated with a worse prognosis. Conclusions: Reduced levels of MALAT1 augment atherosclerotic lesion formation in mice and are associated with human atherosclerotic disease. The proatherosclerotic effects observed in Malat1-/- mice were mainly caused by enhanced accumulation of hematopoietic cells.
KW - atherosclerosis
KW - inflammation
KW - leukocytes
KW - RNA
UR - http://www.scopus.com/inward/record.url?scp=85062265443&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.117.029015
DO - 10.1161/CIRCULATIONAHA.117.029015
M3 - Journal article
C2 - 30586743
AN - SCOPUS:85062265443
SN - 0009-7322
VL - 139
SP - 1320
EP - 1334
JO - Circulation
JF - Circulation
IS - 10
ER -