Angiogenesis inhibitor vasohibin-1 enhances stress resistance of endothelial cells via induction of SOD2 and SIRT1.
Vasohibin-1 (VASH1) is isolated as an endothelial cell (EC)-produced angiogenesis inhibitor. We questioned whether VASH1 plays any role besides angiogenesis inhibition, knocked-down or overexpressed VASH1 in ECs, and examined the changes of EC property. Knock-down of VASH1 induced premature senescence of ECs, and those ECs were easily killed by cellular stresses. In contrast, overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses. The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation. We sought to define the underlying mechanism. VASH1 increased the expression of (superoxide dismutase 2) SOD2, an enzyme known to quench reactive oxygen species (ROS). Simultaneously, VASH1 augmented the synthesis of sirtuin 1 (SIRT1), an anti-aging protein, which improved stress tolerance. Paraquat generates ROS and causes organ damage when administered in vivo. More VASH1 (+/-) mice died due to acute lung injury caused by paraquat. Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat. Thus, VASH1 is a critical factor that improves the stress tolerance of ECs via the induction of SOD2 and SIRT1.
Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Hiroki
H
Miyashita
Tatsuaki
T
Watanabe
Hideki
H
Hayashi
Yasuhiro
Y
Suzuki
Takanobu
T
Nakamura
Soichi
S
Ito
Manabu
M
Ono
Yasushi
Y
Hoshikawa
Yoshinori
Y
Okada
Takashi
T
Kondo
Yasufumi
Y
Sato
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004790:Enzyme Induction; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D012323:RNA Processing, Post-Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000096:biosynthesis*; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D000099156:Superoxide Dismutase 2
D018797:Cell Cycle Proteins; D017931:DNA Primers; D056564:Sirtuin 1; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C493181:VASH1 protein, human; C447939:SIRT1 protein, human