LEONARDO YUJI TANAKA

(Fonte: Lattes)
Índice h a partir de 2011
12
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/64, Hospital das Clínicas, Faculdade de Medicina - Líder

Resultados de Busca

Agora exibindo 1 - 5 de 5
  • article 16 Citação(ões) na Scopus
    Conserved Gene Microsynteny Unveils Functional Interaction Between Protein Disulfide Isomerase and Rho Guanine-Dissociation Inhibitor Families
    (2017) MORETTI, Ana I. S.; PAVANELLI, Jessyca C.; NOLASCO, Patricia; LEISEGANG, Matthias S.; TANAKA, Leonardo Y.; FERNANDES, Carolina G.; WOSNIAK JR., Joao; KAJIHARA, Daniela; DIAS, Matheus H.; FERNANDES, Denise C.; JO, Hanjoong; Ngoc-Vinh Tran; EBERSBERGER, Ingo; BRANDES, Ralf P.; BONATTO, Diego; LAURINDO, Francisco R. M.
    Protein disulfide isomerases (PDIs) support endoplasmic reticulum redox protein folding and cell-surface thiol-redox control of thrombosis and vascular remodeling. The family prototype PDIA1 regulates NADPH oxidase signaling and cytoskeleton organization, however the related underlying mechanisms are unclear. Here we show that genes encoding human PDIA1 and its two paralogs PDIA8 and PDIA2 are each flanked by genes encoding Rho guanine-dissociation inhibitors (GDI), known regulators of RhoGTPases/cytoskeleton. Evolutionary histories of these three microsyntenic regions reveal their emergence by two successive duplication events of a primordial gene pair in the last common vertebrate ancestor. The arrangement, however, is substantially older, detectable in echinoderms, nematodes, and cnidarians. Thus, PDI/RhoGDI pairing in the same transcription orientation emerged early in animal evolution and has been largely maintained. PDI/RhoGDI pairs are embedded into conserved genomic regions displaying common cis-regulatory elements. Analysis of gene expression datasets supports evidence for PDI/RhoGDI coexpression in developmental/inflammatory contexts. PDIA1/RhoGDIa were co-induced in endothelial cells upon CRISP-R-promoted transcription activation of each pair component, and also in mouse arterial intima during flow-induced remodeling. We provide evidence for physical interaction between both proteins. These data support strong functional links between PDI and RhoGDI families, which likely maintained PDI/RhoGDI microsynteny along > 800-million years of evolution.
  • article 17 Citação(ões) na Scopus
    PDIA1 acts as master organizer of NOX1/NOX4 balance and phenotype response in vascular smooth muscle
    (2021) FERNANDES, Denise C.; JR, Joao Wosniak; GONCALVES, Renata C.; TANAKA, Leonardo Y.; FERNANDES, Carolina G.; ZANATTA, Daniela B.; MATTOS, Ana Barbosa M. de; STRAUSS, Bryan E.; LAURINDO, Francisco R. M.
    Changes in vascular smooth muscle cell (VSMC) phenotype underlie disease pathophysiology and are strongly regulated by NOX NADPH oxidases, with NOX1 favoring synthetic proliferative phenotype and NOX4 supporting differentiation. Growth factor-triggered NOX1 expression/activity strictly depends on the chaperone oxidoreductase protein disulfide isomerase-A1 (PDIA1). Intracellular PDIA1 is required for VSMC migration and cytoskeleton organization, while extracellular PDIA1 fine-tunes cytoskeletal mechanoadaptation and vascular remodeling. We hypothesized that PDIA1 orchestrates NOX1/NOX4 balance and VSMC phenotype. Using an inducible PDIA1 overexpression model in VSMC, we showed that early PDIA1 overexpression (for 24-48 h) increased NOX1 expression, hydrogen peroxide steady-state levels and spontaneous VSMC migration distances. Sustained PDIA1 overexpression for 72 h and 96 h supported high NOX1 levels while also increasing NOX4 expression and, remarkably, switched VSMC phenotype to differentiation. Differentiation was preceded by increased nuclear myocardin and serum response factor-response element activation, with no change in cell viability. Both NOX1 and hydrogen peroxide were necessary for later PDIA1-induced VSMC differentiation. In primary VSMC, PDIA1 knockdown decreased nuclear myocardin and increased the proliferating cell nuclear antigen expression. Newly-developed PDIA1 -overexpressing mice (TgPDIA1) exhibited normal general and cardiovascular baseline phenotypes. However, in TgPDIA1 carotids, NOX1 was decreased while NOX4 and calponin expressions were enhanced, indicating overdifferentiation vs. normal carotids. Moreover, in a rabbit overdistension injury model during late vascular repair, PDIA1 silencing impaired VSMC redifferentiation and NOX1/NOX4 balance. Our results suggest a model in which PDIA1 acts as an upstream organizer of NOX1/NOX4 balance and related VSMC phenotype, accounting for baseline differentiation setpoint.
  • article 22 Citação(ões) na Scopus
    Nitroglycerin drives endothelial nitric oxide synthase activation via the phosphatidylinositol 3-kinase/protein kinase B pathway
    (2012) MAO, Mao; SUDHAHAR, Varadarajan; ANSENBERGER-FRICANO, Kristine; FERNANDES, Denise C.; TANAKA, Leonardo Y.; FUKAI, Tohru; LAURINDO, Francisco R. M.; MASON, Ronald P.; VASQUEZ-VIVAR, Jeannette; MINSHALL, Richard D.; STADLER, Krisztian; BONINI, Marcelo G.
    Nitroglycerin (GIN) has been clinically used to treat angina pectoris and acute heart episodes for over 100 years. The effects of GTN have long been recognized and active research has contributed to the unraveling of numerous metabolic routes capable of converting GIN to the potent vasoactive messenger nitric oxide. Recently, the mechanism by which minute doses of GIN elicit robust pharmacological responses was revisited and eNOS activation was implicated as an important route mediating vasodilation induced by low GTN doses (1-50 nM). Here, we demonstrate that at such concentrations the pharmacologic effects of nitroglycerin are largely dependent on the phosphatidylinositol 3-kinase, Akt/PKB, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signal transduction axis. Furthermore, we demonstrate that nitroglycerin-dependent accumulation of 3,4,5-InsP(3), probably because of inhibition of PTEN, is important for eNOS activation, conferring a mechanistic basis for GIN pharmacological action at pharmacologically relevant doses.
  • bookPart
    Forças hemodinâmicas no endotélio: da mecanotransdução às implicações no desenvolvimento da aterosclerose
    (2016) FERNANDES, Denise C.; LAURINDO, Francisco Rafael Martins; ARAUJO, Thaís L. S.; TANAKA, Leonardo Y.
  • conferenceObject
    Protein Disulfide Isomerase A1 is a Central Hub for Redox Regulation of VSMC Phenotype
    (2017) WOSNIAK, Joao; GONCALVES, Renata C.; TANAKA, Leonardo Y.; ZANATTA, Daniela B.; STRAUSS, Bryan E.; LAURINDO, Francisco R.; FERNANDES, Denise C.