Abstract
Background/Objectives Carbonic anhydrase 1 (CA1)/kininogen and selenoprotein W (SelW)/14-3-3η signal transduction orchestrate oxidative stress, which can also be regulated by nitric oxide (NO). The mutated caveolin-1 (Cav-1F92A) gene may enhance NO production. This study explored the effect of Cav-1F92A-modified rat bone marrow mesenchymal stem cells (rBMSC/Cav-1F92A) on oxidative stress regulation through CA1/kininogen and SelW/14-3-3η signal transduction in a rat model of monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Method PAH was induced in rats through the subcutaneous injection of MCT. Next, rBMSC/Vector (negative control), rBMSC/Cav-1, rBMSC/Cav-1F92A, or rBMSC/Cav-1F92A+L-NAME were administered to the rats. Changes in pulmonary hemodynamic and vascular morphometry and oxidative stress levels were evaluated. CA1/kininogen and SelW/14-3-3η signal transduction, endothelial nitric oxide synthase (eNOS) dimerization, and eNOS/NO/sGC/cGMP pathway changes were determined through real-time polymerase chain reaction, Western blot, or immunohistochemical analyses. Results In MCT-induced PAH rats, rBMSC/Cav-1F92A treatment reduced right ventricular systolic pressure, vascular stenosis, and oxidative stress; downregulated CA1/kininogen signal transduction; upregulated SelW/14-3-3η signal transduction; and reactivated the NO pathway. Conclusions In a rat model of MCT-induced PAH, rBMSC/Cav-1F92A reduced oxidative stress by regulating CA1/kininogen and SelW/14-3-3η signal transduction.
Highlights
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease that is associated with a high incidence of morbidity and mortality [1]
We previously found that a mutated caveolin-1 (Cav-1F92A) gene that exhibits an alanine substitution for phenylalanine at position 92 modulates nitric oxide (NO) production in rat bone marrow mesenchymal stem cells [17]
It has been demonstrated the stimulatory effects of Cav-1F92A on angiogenesis in rat bone marrow mesenchymal stem cells (rBMSCs) via improving NO production, which may provide a novel treatment for PAH [17]
Summary
Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease that is associated with a high incidence of morbidity and mortality [1]. SelW, the smallest selenoprotein that contains the canonical amino acid selenocysteine, protects cells against oxidative injury by upregulating 14-3-3η expression [8, 12, 13]. The change in CA1/kininogen and SelW/14-3-3η signal transduction in PAH has never been studied. In rat models of PAH, the MSC-based prostacyclin synthase gene attenuates pulmonary hypertension and improves prognosis [15]. We previously found that a mutated caveolin-1 (Cav-1F92A) gene that exhibits an alanine substitution for phenylalanine at position 92 modulates NO production in rat bone marrow mesenchymal stem cells (rBMSCs) [17]. In the present study, we investigated whether rBMSC/Cav-1F92A can mediate oxidative stress in rats with monocrotaline- (MCT-) induced PAH through the regulation of CA1/kininogen and SelW/14-33η signal transduction
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