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Simvastatin restores pulmonary endothelial function in the setting of pulmonary over-circulation.
Boehme, Jason T; Sun, Xutong; Lu, Qing; Barton, Jubilee; Wu, Xiaomin; Gong, Wenhui; Raff, Gary W; Datar, Sanjeev A; Wang, Ting; Fineman, Jeffrey R; Black, Stephen M.
Afiliação
  • Boehme JT; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Sun X; Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA.
  • Lu Q; Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA.
  • Barton J; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Wu X; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, 85719, USA.
  • Gong W; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Raff GW; Department of Surgery, University of California Davis, Davis, CA, 95817, USA.
  • Datar SA; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Wang T; Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA.
  • Fineman JR; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Black SM; Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA; Department
Nitric Oxide ; 142: 58-68, 2024 Jan 01.
Article em En | MEDLINE | ID: mdl-38061411
ABSTRACT
Statin therapy is a cornerstone in the treatment of systemic vascular diseases. However, statins have failed to translate as therapeutics for pulmonary vascular disease. Early pulmonary vascular disease in the setting of congenital heart disease (CHD) is characterized by endothelial dysfunction, which precedes the more advanced stages of vascular remodeling. These features make CHD an ideal cohort in which to re-evaluate the potential pulmonary vascular benefits of statins, with a focus on endothelial biology. However, it is critical that the full gamut of the pleiotropic effects of statins in the endothelium are uncovered. The purpose of this investigation was to evaluate the therapeutic potential of simvastatin for children with CHD and pulmonary over-circulation, and examine mechanisms of simvastatin action on the endothelium. Our data demonstrate that daily simvastatin treatment preserves endothelial function in our shunt lamb model of pulmonary over-circulation. Further, using pulmonary arterial endothelial cells (PAECs) isolated from Shunt and control lambs, we identified a new mechanism of statin action mediated by increased expression of the endogenous Akt1 inhibitor, C-terminal modifying protein (CTMP). Increases in CTMP were able to decrease the Akt1-mediated mitochondrial redistribution of endothelial nitric oxide synthase (eNOS) which correlated with increased enzymatic coupling, identified by increases in NO generation and decreases in NOS-derived superoxide. Together our data identify a new mechanism by which simvastatin enhances NO signaling in the pulmonary endothelium and identify CTMP as a potential therapeutic target to prevent the endothelial dysfunction that occurs in children born with CHD resulting in pulmonary over-circulation.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Vasculares / Inibidores de Hidroximetilglutaril-CoA Redutases Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Vasculares / Inibidores de Hidroximetilglutaril-CoA Redutases Idioma: En Ano de publicação: 2024 Tipo de documento: Article