Yui Takahashi1, Rena Watanabe1, Yuki Sato1, Nana Ozawa1, Miho Kojima1, Kaho Watanabe-Kominato1, Remina Shirai1, Kengo Sato1, Tsutomu Hirano2, Takuya Watanabe3. 1. Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan. 2. Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan. 3. Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan. Electronic address: watanabe@toyaku.ac.jp.
Abstract
INTRODUCTION: The novel phytohormone, osmotin, has been reported to act like mammalian adiponectin through PHO36/AdipoR1 in various in vitro and in vivo models. However, there have been no reports regarding the precise effects of osmotin on atherosclerosis. METHODS: We assessed the atheroprotective effects of osmotin on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), human leukemic monocyte (THP-1) adhesion, inflammatory responses, and foam cell formation in THP-1-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs). We examined whether 4-week infusion of osmotin could suppress the development of aortic atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice. RESULTS: AdipoR1 was abundantly expressed in HUVECs, HASMCs, THP-1, and derived macrophages. Osmotin suppressed lipopolysaccharide-induced upregulation of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin in HUVECs, and TNF-α-induced THP-1-HUVEC adhesion. In THP-1-derived macrophages, osmotin suppressed the inflammatory M1 phenotype, lipopolysaccharide-induced secretion of interleukin-6 and TNF-α, and oxidized low-density lipoprotein-induced foam cell formation associated with CD36 and acyl-CoA:cholesterol acyltransferase 1 downregulation and ATP-binding cassette transporter A1 upregulation. In HASMCs, osmotin suppressed angiotensin II-induced migration, proliferation, collagen-1 and fibronectin expression, and matrix metalloproteinase-2 activity without inducing apoptosis. Infusion of osmotin into ApoE-/- mice prevented the development of aortic atherosclerotic lesions with reductions of intraplaque pentraxin-3 expression, fasting plasma glucose, and insulin resistance. CONCLUSIONS: This study provided the first evidence that osmotin exerts preventive effects on vascular inflammation and atherosclerosis, which may facilitate the development of new therapeutic modalities for combating atherosclerosis and related diseases.
INTRODUCTION: The novel phytohormone, osmotin, has been reported to act like mammalianadiponectin through PHO36/AdipoR1 in various in vitro and in vivo models. However, there have been no reports regarding the precise effects of osmotin on atherosclerosis. METHODS: We assessed the atheroprotective effects of osmotin on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), humanleukemic monocyte (THP-1) adhesion, inflammatory responses, and foam cell formation in THP-1-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs). We examined whether 4-week infusion of osmotin could suppress the development of aortic atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice. RESULTS:AdipoR1 was abundantly expressed in HUVECs, HASMCs, THP-1, and derived macrophages. Osmotin suppressed lipopolysaccharide-induced upregulation of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin in HUVECs, and TNF-α-induced THP-1-HUVEC adhesion. In THP-1-derived macrophages, osmotin suppressed the inflammatory M1 phenotype, lipopolysaccharide-induced secretion of interleukin-6 and TNF-α, and oxidized low-density lipoprotein-induced foam cell formation associated with CD36 and acyl-CoA:cholesterol acyltransferase 1 downregulation and ATP-binding cassette transporter A1 upregulation. In HASMCs, osmotin suppressed angiotensin II-induced migration, proliferation, collagen-1 and fibronectin expression, and matrix metalloproteinase-2 activity without inducing apoptosis. Infusion of osmotin into ApoE-/- mice prevented the development of aortic atherosclerotic lesions with reductions of intraplaque pentraxin-3 expression, fasting plasma glucose, and insulin resistance. CONCLUSIONS: This study provided the first evidence that osmotin exerts preventive effects on vascular inflammation and atherosclerosis, which may facilitate the development of new therapeutic modalities for combating atherosclerosis and related diseases.
Authors: Jun Chen; Xixi Zhang; Reid Millican; Jennifer Sherwood; Sean Martin; Hanjoong Jo; Young-Sup Yoon; Brigitta C Brott; Ho-Wook Jun Journal: Adv Drug Deliv Rev Date: 2021-01-09 Impact factor: 15.470