Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension

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Camargo, Livia De Lucca ; Trevelin, Silvia Cellone ; da Silva, Guilherme Henrique Gatti ; Dias, Ana Alice dos Santos ; Oliveira, Maria Aparecida ; Mikhaylichenko, Olga ; Androwiki, Aline C. D. ; dos Santos, Celio Xavier ; Holbrook, Lisa-Marie ; Ceravolo, Graziela Scalianti ; Denadai-Souza, Alexandre ; Ribeiro, Izabela Martina Ramos ; Sartoretto, Simone ; Laurindo, Francisco Rafael Martins ; Coltri, Patricia Pereira ; Antunes, Vagner Roberto ; Touyz, Rhian ; Miller Jr, Francis J. ; Shah, Ajay M. ; Lopes, Lucia Rossetti

• Tipo de documento: Artigo Científico
• Fonte: Journal of Hypertension; v. 42, n. 6, p. 16-pg., 2024-06-01.

Resumo

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease. (AU)

• Processo FAPESP: 20/12432-6 - Investigação dos mecanismos redox dependentes envolvidos na resistência ao Vemurafenibe em células de Melanoma
• Beneficiário: Lucia Rossetti Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/21874-5 - Regulação do splicing de miRNAs no Câncer
• Beneficiário: Patricia Pereira Coltri
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/19894-8 - Caracterização neuroanatômica e funcional da sinalização purinérgica em núcleos hipotalâmicos envolvidos no controle de fluidos corpóreos e hipertensão neurogênica decorrente da alta ingestão de sal
• Beneficiário: Vagner Roberto Antunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/03520-5 - Papel da proteína dissulfeto isomerase na geração de espécies reativas de oxigênio pela NADPH oxidase durante o desenvolvimento da hipertensão arterial
• Beneficiário: Lucia Rossetti Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Regular