rBMSC/Cav-1^F92A Mediates Oxidative Stress in PAH Rat by Regulating SelW/14-3-3η and CA1/Kininogen Signal Transduction

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.

Phoenixin 20 ameliorates pulmonary arterial hypertension via inhibiting inflammation and oxidative stress

“…Increased ROS further reduces the synthesis of NO by inhibiting eNOS activity to aggravate vascular endothelial OS injury, which promotes the proliferation and migration of vascular smooth muscle cells and accelerates vascular remodeling. In our study, OS was found activated in both lung tissues of PAH rats and hypoxia-stimulated PMECs, which was consistent with data presented by Wang [ 23 ] and Yu [ 24 ]. After PHN-20 treatment, OS was signally repressed in both lung tissues of PAH rats and hypoxia-stimulated PMECs, implying that the alleviative effect of PHN-20 against PAH might be correlated with the inhibition of OS.…”

Oxidative Stress and Antioxidative Therapy in Pulmonary Arterial Hypertension

“…The arginine-NOS-NO pathway is important in the regulation and remodeling of PAH vascular tension. Recent studies have shown that the carbonic anhydrase 1-kininogen and selenium protein W/14-3-3 signaling pathway attenuates the inhibitory effect on eNOS, promotes NO production, and regulates oxidative stress in Monocrotaline (MCT)-induced rat models [31]. During the first week in the MCT model, nitrosative stress leads to adaptation of NOS activity to later increase NO production after two weeks.…”

Dissecting molecular mechanisms underlying ferroptosis in human umbilical cord mesenchymal stem cells: Role of cystathionine γ-lyase/hydrogen sulfide pathway

“…qPCR was performed as previously described[ 15 , 17 ]. Human GAPDH expression was used for normalization.…”

“…Whole-cell, cytosolic, and nuclear proteins were extracted using RIPA Lysis and Extraction Buffer (89900, Thermo Fisher Scientific, United States) or NE-PER Nuclear and Cytoplasmic Extraction Reagents (78835, Thermo Fisher Scientific, United States). The extractions were performed as previously described[ 17 ]. Primary antibodies against the following were used: Glutathione peroxidase 4 (GPX4, 1:1000, 59735S, CST), intracellular ferritin heavy chain 1 (FTH1, 1:1000, 4393S, CST), nuclear receptor coactivator 4 (NOCA4, 1:1000, 66849S, CST), Fe 3+ -bound transferrin receptor 1 (TFRC1, 1:1000, ab214039, Abcam), 4-hydroxynonenal (4-HNE, 1:1000, ab46545, Abcam), SLC7A11 (1:1000, ab175186, Abcam), Nrf2 (1:1000, ab62352, Abcam), Keap1 (sc-365626, Santa Cruz Biotechnology), CSE (1:1000, 19689S, CST), GAPDH (1:1000, 5174S, CST), and Histone H3 (1:1000, ab1791, Abcam).…”