GUSTAVO KEN HIRONAKA

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina

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Agora exibindo 1 - 3 de 3
  • conferenceObject
    Peri/epicellular Protein Disulfide Isomerase Reshapes Vascular Architecture to Counteracts Constrictive Remodeling
    (2014) TANAKA, Leonardo Yuji; ARAUJO, Haniel Alves; HIRONAKA, Gustavo Ken; ARAUJO, Thais Larissa; RODRIGUEZ, Andres Ignacio; CASAGRANDE, Annelise Silva; TAKIMURA, Celso Kiyoshi; LAURINDO, Francisco Rafael
  • article 34 Citação(ões) na Scopus
    Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect
    (2016) TANAKA, Leonardo Y.; ARAUJO, Haniel A.; HIRONAKA, Gustavo K.; ARAUJO, Thais L. S.; TAKIMURA, Celso K.; RODRIGUEZ, Andres I.; CASAGRANDE, Annelise S.; GUTIERREZ, Paulo S.; LEMOS-NETO, Pedro Alves; LAURINDO, Francisco R. M.
    Whole-vessel remodeling critically determines lumen caliber in vascular (patho)physiology, and it is reportedly redox-dependent. We hypothesized that the cell-surface pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (peri/epicellular=pecPDI), which is known to support thrombosis, also regulates disease-associated vascular architecture. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling and plaque stability. In a rabbit iliac artery overdistension model, there was unusually high PDI upregulation (approximate to 25-fold versus basal, 14 days postinjury), involving both intracellular and pecPDI. PecPDI neutralization with distinct anti-PDI antibodies did not enhance endoplasmic reticulum stress or apoptosis. In vivo pecPDI neutralization with PDI antibody-containing perivascular gel from days 12 to 14 post injury promoted 25% decrease in the maximally dilated arteriographic vascular caliber. There was corresponding whole-vessel circumference loss using optical coherence tomography without change in neointima, which indicates constrictive remodeling. This was accompanied by decreased hydrogen peroxide generation. Constrictive remodeling was corroborated by marked changes in collagen organization, that is, switching from circumferential to radial fiber orientation and to a more rigid fiber type. The cytoskeleton architecture was also disrupted; there was a loss of stress fiber coherent organization and a switch from thin to medium thickness actin fibers, all leading to impaired viscoelastic ductility. Total and PDI-associated expressions of 1-integrin, and levels of reduced cell-surface 1-integrin, were diminished after PDI antibody treatment, implicating 1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream 1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to counteract inward remodeling in vascular pathophysiology.
  • conferenceObject
    Role of Protein Disulfide Isomerase during vascular repair after injury
    (2012) TANAKA, Leonardo Yuji; ARAUJO, Haniel Alves; CSORDAS, Andre Alcantara; HIRONAKA, Gustavo Ken; TAKIMURA, Celso Kiyochi; LAURINDO, Francisco Rafael Martins
    Endoplasmic reticulum(ER) redox chaperone protein disulfide isomerase(PDI) regulates vascular/phagocytic NADPH oxidase and supports cell migration. We investigated the role of PDI during vascular repair after injury(AI) induced by balloon in rabbit iliac artery. There was marked increase of PDI mRNA and protein(5–10-fold) at 4, 7 and 14 days AI vs. intact control(CT). PDI immunostaining was greater in intima = neo-endothelium > media. Increased cell-surface PDI was also evident. ER stress-related KDEL chaperones also increased with similar time-course AI. PDI siRNA(siPDI) transfection in cultured vessel rings collected 14 days AI enhanced KDEL expression vs. scrambled siRNA(siScr) (siScr 2.1±0.9 vs. siPDI 5.0±2.3-fold vs. CT, p<0.05), apoptosis (siScr 4.6±0.2 vs. siPDI 6.2±0.9 %TUNEL + nuclei, p<0.05) and proliferation marker PCNA (siScr 1.2±0.3 vs. siPDI 4.0 ±0.2 AU, p<0.05), and decreased differentiation marker calponin-C (siScr 0.52±0.04 vs. siPDI 0.36 ±0.04 AU, p<0.05). siPDI in CT rings did not alter such variables. PCR array analysis showed analogous pattern of mRNA changes. Also, siPDI 14 days AI upregulated Nox1 and downregulated Nox4 NADPH oxidase, while siPDI attenuated oxidant production (in situ hydroethidine) only in CT vessels. Thus, strongly-overexpressed PDI 14 days AI protects against apoptosis and ER stress and sustains VSMC differentiation.