LEONARDO YUJI TANAKA
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/64, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/64, Hospital das Clínicas, Faculdade de Medicina - Líder
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
- 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.
- 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.
- Effects of static magnetic field on vascular function and structure and their potential implications with redox regulation of actin cytoskeleton(2023) MASSUCATTO, Ricardo; BAHARAMI, Abasalt; GUTIERRE, Lucas; AIELLO, Clarice; LAURINDO, Francisco R.; TANAKA, Leonardo
- Disturbed flow regulates protein disulfide isomerase A1 expression via microRNA-204(2024) TANAKA, Leonardo Y.; KUMAR, Sandeep; GUTIERRE, Lucas F.; MAGNUN, Celso; KAJIHARA, Daniela; KANG, Dong-Won; LAURINDO, Francisco R. M.; JO, HanjoongRedox processes can modulate vascular pathophysiology. The endoplasmic reticulum redox chaperone protein disulfide isomerase A1 (PDIA1) is overexpressed during vascular proliferative diseases, regulating thrombus formation, endoplasmic reticulum stress adaptation, and structural remodeling. However, both protective and deleterious vascular effects have been reported for PDIA1, depending on the cell type and underlying vascular condition. Further understanding of this question is hampered by the poorly studied mechanisms underlying PDIA1 expression regulation. Here, we showed that PDIA1 mRNA and protein levels were upregulated (average 5-fold) in the intima and media/adventitia following partial carotid ligation (PCL). Our search identified that miR-204-5p and miR-211-5p (miR-204/211), two broadly conserved miRNAs, share PDIA1 as a potential target. MiR-204/211 was downregulated in vascular layers following PCL. In isolated endothelial cells, gain-of-function experiments of miR-204 with miR mimic decreased PDIA1 mRNA while having negligible effects on markers of endothelial activation/stress response. Similar effects were observed in vascular smooth muscle cells (VSMCs). Furthermore, PDIA1 downregulation by miR-204 decreased levels of the VSMC contractile differentiation markers. In addition, PDIA1 overexpression prevented VSMC dedifferentiation by miR-204. Collectively, we report a new mechanism for PDIA1 regulation through miR-204 and identify its relevance in a model of vascular disease playing a role in VSMC differentiation. This mechanism may be regulated in distinct stages of atherosclerosis and provide a potential therapeutic target.