title: Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state.
abstract: Ageing is an important risk factor for ischemic cardiovascular diseases, although its underlying molecular mechanisms remain to be elucidated. Here, we report a crucial role of Bcl-2 in the impaired angiogenic functions in senescent endothelial cells (ECs) by modulating the mitochondrial redox state. Cellular senescence impaired angiogenic functions in ECs without attenuating the mitogen-activated protein kinase or Akt signaling, and vascular endothelial growth factor receptor 2 or Tie-2 expressions. We identified that Bcl-2 expression was markedly reduced in 3 independent models for senescent ECs, and pharmacological inhibition, as well as small interfering RNA-mediated gene silencing of Bcl-2, significantly impaired the angiogenic functions in young ECs. Bcl-2 has an antioxidative role by locating the glutathione at mitochondria, and we found that mitochondrial oxidative stress was significantly augmented in senescent ECs, in association with reduced mitochondria-associated glutathione. Transfection of Bcl-2 in senescent ECs significantly reduced the mitochondrial oxidative stress, restored the mitochondrial membrane potential, and improved the angiogenic capacity. Furthermore, gene transfer of Bcl-2 using adenovirus significantly improved the in vivo angiogenesis in the Matrigel plugs implanted into aged mice, whereas the Bcl-2 inhibitor reduced the angiogenesis in the Matrigel plugs implanted into young mice. Together, Bcl-2 plays a crucial role in the regulation of the mitochondrial redox state in ECs, and, thus, loss of Bcl-2 during the senescence exacerbates the impaired angiogenesis by augmenting the mitochondrial oxidative stress.
authors: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566, Japan.
authors: Maki
authors: M
authors: Uraoka
authors: Koji
authors: K
authors: Ikeda
authors: Ritsuko
authors: R
authors: Kurimoto-Nakano
authors: Yusuke
authors: Y
authors: Nakagawa
authors: Masahiro
authors: M
authors: Koide
authors: Yoshiki
authors: Y
authors: Akakabe
authors: Youhei
authors: Y
authors: Kitamura
authors: Tomomi
authors: T
authors: Ueyama
authors: Satoaki
authors: S
authors: Matoba
authors: Hiroyuki
authors: H
authors: Yamada
authors: Mitsuhiko
authors: M
authors: Okigaki
authors: Hiroaki
authors: H
authors: Matsubara
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases