title: Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice.
abstract: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension.
  
  
  
  The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure.
  
  
  
  LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Le
authors: L
authors: Jiang
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.). konishi@juntendo.ac.jp.
authors: Hakuoh
authors: H
authors: Konishi
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Fariz
authors: F
authors: Nurwidya
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Kimio
authors: K
authors: Satoh
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Fumiyuki
authors: F
authors: Takahashi
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Hiroyuki
authors: H
authors: Ebinuma
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Kengo
authors: K
authors: Fujimura
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Kiyoshi
authors: K
authors: Takasu
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Meizi
authors: M
authors: Jiang
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Hiroaki
authors: H
authors: Shimokawa
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Hideaki
authors: H
authors: Bujo
authors: From the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (L.J., H.K., K.T., H.D.); Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan (F.N., F.T.); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., H.S.); Tsukuba Research Institute, Sekisui Medical Co Ltd, Ryugasaki, Japan (H.E., K.F.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (M.J., H.B.).
authors: Hiroyuki
authors: H
authors: Daida
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D049109:Cell Proliferation; D002478:Cells, Cultured; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D066253:Vascular Remodeling; D014655:Vascular Resistance; D018497:Ventricular Dysfunction, Right / Q000378:metabolism / Q000517:prevention & control; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse
keywords: LR11/SorLA; atherosclerosis; biomarkers; disease progression; pulmonary hypertension; vascular smooth muscle