Abstract P094: Crosstalk Between Mas And ET B R Elicits Protective Effects In Endothelial Cells And Vascular Function

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jithin Kuriakose ◽  
Augusto C Montezano ◽  
Katie Y Hood ◽  
Rheure Alves-lopes ◽  
Angie Sin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Mrna Expression ◽  
Vascular Function ◽  
Superoxide Anion ◽  
High Throughput Screening ◽  
No Production ◽  
Protective Effects ◽  
Amplex Red ◽  
Protective Actions

Mas and ET B receptors physically interact in endothelial cells (ECs) and are involved in the protective actions of angiotensin 1-7 (Ang (1-7)). We assessed whether the MAS/ET B R interaction plays a role in EC signalling and whether strategies to enhance MAS/ET B R association influence vascular responses. Human ECs were stimulated with Ang (1-7) (10 -7 M) in the presence/absence of A779 (Mas receptor antagonist, 10 -5 M) and BQ788 (ET B R antagonist, 10 -5 M). Protein expression and signalling activation were assessed by immunoblotting. NO production was evaluated by DAF-FM fluorescence and ROS production by chemiluminescence (superoxide anion) or amplex red (hydrogen peroxide (H 2 O 2 )). mRNA expression was assessed by qPCR. Endothelial function was assessed in mouse intact arteries by myography. Ang (1-7), through Mas and ET B R induced phosphorylation of eNOS (35%); followed by an increase in NO production (2.0 fold) (p<0.05 vs ctl). High throughput screening of protein:protein interaction compounds in an in-house library identified 23 potential enhancers of the MAS/ET B R interaction. Fluorescence polarization assays were used to further select the most potent enhancers and define their working concentration for testing in ECs (Enh1-4: 10 -5 M). Enh4 increased superoxide anion (55.6±26.3% vs ctl, p<0.05) and H 2 O 2 production (54.7±11.1% vs ctl, p<0.05), while Enh3 increased H 2 O 2 generation (48.1±15.4% vs ctl, p<0.05) in ECs. Moreover, Enh4 increased Nrf2 (3.0 fold), Sod1 (2.0 fold) and Nqo1 (3.1 fold) mRNA expression (p<0.05 vs ctl). Enh3 and Enh4 increased NO production (Enh3: 21.2±7.4%; Enh4: 23.6±8.2% vs veh, p<0.05) in ECs. Acetylcholine (Ach) curves were performed to assess endothelium-dependent relaxation in the absence and presence of enhancers. Enh4 increased ACh-induced relaxation (Emax%: 96.7±4.6 vs ctl: 70.4±3.3, p<0.05), while other enhancers did not improve endothelial function. Taken together, increasing MAS/ET B R interaction with specific enhancers augments protective signalling in ECs and promotes endothelial-dependent vasorelaxation, particularly with Enh4. In conclusion, enhancing interactions between MasR and ET B R may be a new vasoprotective strategy to improve vascular function in cardiovascular disease.

scholarly journals Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

2016 ◽  
Vol 310 (11) ◽  
pp. E947-E957 ◽  
Author(s):  
Rui Wei ◽  
Shifeng Ma ◽  
Chen Wang ◽  
Jing Ke ◽  
Jin Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
No Production ◽  
Dependent Manner ◽  
Protective Effects ◽  
Newly Diagnosed ◽  
Coronary Endothelial Function ◽  
Enos Phosphorylation

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

scholarly journals Inhibition of Autophagy by Chloroquine Stimulates Nitric Oxide Production and Protects Endothelial Function during Serum Deprivation

2015 ◽  
Vol 37 (3) ◽  
pp. 1168-1177 ◽  
Author(s):  
Cezar Rangel Pestana ◽  
Jorge Camargo Oishi ◽  
Heloísa Sobreiro Salistre-Araújo ◽  
Gerson Jhonatan Rodrigues
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Vascular Function ◽  
Ex Vivo ◽  
Aortic Ring ◽  
Serum Deprivation ◽  
Nutrient Deprivation ◽  
No Production ◽  
Sequestosome 1

Background/Aims: Autophagy plays a fundamental role in cell survival under stress conditions such as nutrient deprivation. Decreased nitric oxide (NO) production, which may contribute to vascular dysfunction, is one of the consequences of autophagy in endothelial cells. The antimalarial drug chloroquine (CLQ) inhibits autophagy by blocking autophagosome formation and has been proposed as adjuvant chemotherapy in other diseases. Methods: Autophagy was induced by serum deprivation in Human Umbilical Vascular Endothelial Cells (HUVEC) as demonstrated by formation of Acidic Vesicular Organelles (AVOs), conversion of Microtubule-associated protein 1 light chain (LC3), and Sequestosome-1 (SQTM1/p62) degradation. Using endothelium-dependent vasorelaxation assays, intracellular NO production in an ex vivo rat aortic ring model pre-constricted with phenylephrine was estimated along with DAF-2 DA cell membrane-permeable NO sensitive fluorescent dye. Results: The inhibition of autophagy by CLQ restored NO levels, protected against superoxide generation and preserved morphology as well as proliferation of HUVEC under serum deprivation. Interestingly, the incubation of rat aortic rings with CLQ resulted in endothelium-dependent relaxation mediated by the increase of NO. Conclusion: These findings emphasize the importance of autophagy in endothelial function and demonstrate the potential use of autophagy inhibitors to protect vascular function during nutrient deprivation.

Stimulation of Tetrahydrobiopterin Synthesis by 17β-Estradiol in Brain Microvascular Endothelial Cells

Pteridines ◽  
2000 ◽  
Vol 11 (4) ◽  
pp. 129-132
Author(s):  
Kazuhiro Shiota ◽  
Masakazu Ishii ◽  
Toshinori Yamamoto ◽  
Shunichi Shimizu ◽  
Yuji Kiuchi
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Vascular Endothelial Cells ◽  
Mrna Level ◽  
Microvascular Endothelial Cells ◽  
No Production ◽  
Brain Microvascular Endothelial Cells ◽  
Protective Effects ◽  
17Β Estradiol ◽  
Microvascular Endothelial

Abstract The purpose of this study was to examine whether 17β-estradiol stimulates the synthesis of tetrahydrobiopterin : BH4), which is one of the cofactors of nitric oxide (NO) synthase, in mouse brain microvascular endothelial cells. Addition of 17()-estradiol to endothelial cells time- and concentration-dependently increased intracellular BH4 level. 17β-Estradiol also stimulated the mRNA level of GTP-cyclohydrolase I (GTPCH), which is a rate-limiting enzyme of the de novo BH4 synthetic pathway. In addition, the 17β-estradiol-induced expression of GTPCH mRNA was strongly attenuated by treatment with an inhibitor of 17β-estradiol receptor 4-hydroxy-tamoxlfen. These results suggest that 17β-estradiol stimulates BH4 synthesis through the induction of GTPCH by tamoxifensensitive receptor in vascular endothelial cells. The 17β-estradiol-induced increase in BH4 level might be implicated in not only NO production, but also protective effects of 17β-estradiol against ischemic brain damage and atherosclerosis, since BH4 is an intracellular antioxidant.

scholarly journals Cadmium reduces nitric oxide production by impairing phosphorylation of endothelial nitric oxide synthase

2008 ◽  
Vol 86 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Syamantak Majumder ◽  
Ajit Muley ◽  
Gopi Krishna Kolluru ◽  
Samir Saurabh ◽  
K. P. Tamilarasan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Egg Yolk ◽  
Cellular Migration ◽  
No Production ◽  
Enos Phosphorylation ◽  
Low Levels ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Cadmium (Cd) perturbs vascular health and interferes with endothelial function. However, the effects of exposing endothelial cells to low doses of Cd on the production of nitric oxide (NO) are largely unknown. The objective of the present study was to evaluate these effects by using low levels of CdCl2 concentrations, ranging from 10 to 1000 nmol/L. Cd perturbations in endothelial function were studied by employing wound-healing and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. The results suggest that a CdCl2 concentration of 100 nmol/L maximally attenuated NO production, cellular migration, and energy metabolism in endothelial cells. An egg yolk angiogenesis model was employed to study the effect of Cd exposure on angiogenesis. The results demonstrate that NO supplementation restored Cd-attenuated angiogenesis. Immunofluorescence, Western blot, and immuno-detection studies showed that low levels of Cd inhibit NO production in endothelial cells by blocking eNOS phosphorylation, which is possibly linked to processes involving endothelial function and dysfunction, including angiogenesis.

scholarly journals L-sepiapterin restores SLE serum-induced markers of endothelial function in endothelial cells

2019 ◽  
Vol 6 (1) ◽  
pp. e000294 ◽  
Author(s):  
Joy N Jones Buie ◽  
Dorea Pleasant Jenkins ◽  
Robin Muise-Helmericks ◽  
Jim C Oates
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Mrna Expression ◽  
Neutrophil Migration ◽  
Basal Medium ◽  
Neutrophil Adhesion ◽  
No Production ◽  
Functional Changes ◽  
Enos Mrna ◽  
The Impact

ObjectiveSLE serves as an independent risk factor` for endothelial dysfunction (ED) not explained by Framingham risk factors. We sought to understand the development of SLE-induced ED on a cellular level in order to develop strategies aimed at reversing cellular abnormalities. This study assessed the impact of SLE patient serum on endothelial nitric oxide synthase (eNOS), nitric oxide (NO) production and functional changes in the cell.MethodsHuman umbilical vein endothelial cells (HUVECs) cultured in serum of either SLE (n=25) or healthy patients (n=14) or endothelial basal medium 2 (EBM-2) culture media supplemented with fetal bovine serum with or without L-sepiapterin were used for our studies. We applied the fluorescent probe DAF-FM diacetate for intracellular NO detection using flow cytometry. Total RNA isolates were analysed using reverse transcription PCR for eNOS mRNA expression. Oxygen consumption rate was determined using seahorse analysis. Neutrophil adhesion and migration were determined using a calcein AM microscopy assay.ResultsThe mRNA expression of eNOS was increased in SLE cultured HUVECs compared with healthy control (p<0.05). The SLE eNOS mRNA level correlated with SLE patient age (p=0.008); however, this trend was not observed with healthy patients. SLE serum reduced NO production in HUVECs compared with EBM-2 cultured cells (p<0.05). Co-treatment of endothelial cells with L-sepiapterin preserved HUVEC capacity to produce NO in SLE conditions (p<0.01). SLE serum enhanced neutrophil migration (p<0.01) but not neutrophil adhesion compared with healthy controls. The bioenergetic health index was not different.ConclusionsSLE likely causes disruption of endothelial cell eNOS function and NO modulated pathways.

Abstract MP29: Activation Of Transient Receptor Potential Melastatin 2 (trpm2) Cation Channel Contributes To Nox4-induced Protective Effects In Endothelial Cells.

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Rheure Alves-Lopes ◽  
Karla B Neves ◽  
Adam Harvey ◽  
Augusto C Montezano ◽  
Rhian M Touyz
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Protective Effects ◽  
Ang Ii ◽  
Vascular Relaxation ◽  
Resistance Arteries ◽  
Transient Receptor Potential Melastatin

NOX4-induced H 2 O 2 production promotes vasodilation and is cardiovascular protective. H 2 O 2 also regulates TRPM2, a redox-sensitive channel that regulates Ca 2 influx. eNOS is a Ca 2+ -dependent enzyme, and hypertension-associated endothelial dysfunction involves eNOS inactivation. As NOX4-derived H 2 O 2 regulates TRPM2 and consequently Ca 2+ influx, we questioned whether downregulation of the H 2 O 2 -TRPM2-Ca 2+ axis in endothelial cells may contributes to impaired vascular relaxation in hypertension. WT and TTRhRen hypertensive mice were crossed with Nox4 KO mice. Vascular function was studied in mesenteric resistance arteries by wire myography. Ca 2+ influx was assessed by fluorescence microscopy in aortic endothelial cells, eNOS activation and TRPM2 expression were assessed by immunoblotting and immunohistochemistry, respectively. Blood pressure in TTRhRen (130.3±7.0 mmHg) and TTRhRen/NOX4 KO mice (141.3±18 mmHg) was significantly increased compared to control mice (98.1±8.0 mmHg). Endothelium-dependent relaxation was impaired in TTRhRen mice (Emax: WT 83.5±4.03 vs TTRhRen 59.1±3.5), effects worsened by NOX4 KO (37.9±5.4), p<0.05. Activation of TRPM2 with ADPR, improved vascular relaxation in TTRhRen/NOX4 KO mice (75.9±7.7); an effect also achieved with H 2 O 2 incubation (74.2±15.4), p<0.05. Ang II stimulated H 2 O 2 generation (% of control: 138.23±9.04) followed by Ca 2+ influx (AUC - Ca 2+ : 19401.25±1940.21), an important regulator of eNOS. These processes were reduced by TRPM2 inhibition (AUC - Ca 2+ : 8-br-cADPR 15232.2±1052.0; Olaparib 14260±843.2 and 2-APB 13095.2±277.4, p<0.05) and by the NOX1/4 inhibitor GKT137831 (AUC - Ca 2+ : Ang II 107357±1940.2 vs GKT 15067.5±255.6, p<0.05). Activation of eNOS (Ser1177) by Ang II in endothelial cells was blocked by PEG-catalase, GKT137831, and the TRPM2 inhibitor 8-br-cADPR. TRPM2 inhibitors also increased MAPK expression in endothelial cells. In conclusion, endothelial dysfunction in TTRhRen/NOX4 KO mice involves impaired TRPM2 activation. Reduced bioavailability of H 2 O 2 due to Nox4 downregulation is a major driver of this process. We identify a new axis in endothelial cells involving Nox4-H 2 O 2 -mediated activation of TRPM2-Ca 2+ -eNOS signalling which is vasoprotective.

scholarly journals NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives

2007 ◽  
Vol 293 (4) ◽  
pp. H2320-H2327 ◽  
Author(s):  
Joon-Young Park ◽  
Iain K. G. Farrance ◽  
Nicola M. Fenty ◽  
James M. Hagberg ◽  
Stephen M. Roth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Function ◽  
Intracellular Signaling ◽  
Vascular Function ◽  
Stage I ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Nos3 Gene

In endothelial cells, NF-κB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase ( NOS3) gene expression. We investigated whether NF-κ light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (−94 NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage I hypertensive individuals before and after a 6-mo supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the −94 NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity.

scholarly journals Protective Effects of Rhodiola Crenulata Extract on Hypoxia-Induced Endothelial Damage via Regulation of AMPK and ERK Pathways

2018 ◽  
Vol 19 (8) ◽  
pp. 2286 ◽  
Author(s):  
Pi-Kai Chang ◽  
I-Chuan Yen ◽  
Wei-Cheng Tsai ◽  
Tsu-Chung Chang ◽  
Shih-Yu Lee
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Umbilical Vein ◽  
Hypoxic Exposure ◽  
No Production ◽  
Root Extract ◽  
Protective Effects ◽  
Rhodiola Crenulata

Rhodiola crenulata root extract (RCE) has been shown to possess protective activities against hypoxia both in vitro and in vivo. However, the effects of RCE on response to hypoxia in the endothelium remain unclear. In this study, we aimed to examine the effects of RCE in endothelial cells challenged with hypoxic exposure and to elucidate the underlying mechanisms. Human umbilical vein endothelial cells were pretreated with or without RCE and then exposed to hypoxia (1% O2) for 24 h. Cell viability, nitric oxide (NO) production, oxidative stress markers, as well as mechanistic readouts were studied. We found that hypoxia-induced cell death, impaired NO production, and oxidative stress. These responses were significantly attenuated by RCE treatment and were associated with the activation of AMP-activated kinase and extracellular signal-regulated kinase 1/2 signaling pathways. In summary, we showed that RCE protected endothelial cells from hypoxic insult and suggested that R. crenulata might be useful for the prevention of hypoxia-associated vascular dysfunction.

scholarly journals Resveratrol and Vascular Function

2019 ◽  
Vol 20 (9) ◽  
pp. 2155 ◽  
Author(s):  
Li ◽  
Xia ◽  
Hasselwander ◽  
Daiber
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Vascular Function ◽  
Cell Function ◽  
Immune Cell ◽  
Sirtuin 1 ◽  
Protective Effects ◽  
Vascular Effects ◽  
Perivascular Adipose Tissue ◽  
Enos Uncoupling

Resveratrol increases the production of nitric oxide (NO) in endothelial cells by upregulating the expression of endothelial NO synthase (eNOS), stimulating eNOS enzymatic activity, and preventing eNOS uncoupling. At the same time, resveratrol inhibits the synthesis of endothelin-1 and reduces oxidative stress in both endothelial cells and smooth muscle cells. Pathological stimuli-induced smooth muscle cell proliferation, vascular remodeling, and arterial stiffness can be ameliorated by resveratrol as well. In addition, resveratrol also modulates immune cell function, inhibition of immune cell infiltration into the vascular wall, and improves the function of perivascular adipose tissue. All these mechanisms contribute to the protective effects of resveratrol on vascular function and blood pressure in vivo. Sirtuin 1, AMP-activated protein kinase, and estrogen receptors represent the major molecules mediating the vascular effects of resveratrol.

scholarly journals Human Tissue Kallikrein 1 Is Downregulated in Elderly Human Prostates and Possesses Potential In Vitro Antioxidative and Antifibrotic Effects in Rodent Prostates

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Mengyang Zhang ◽  
Changcheng Luo ◽  
Dongxu Lin ◽  
Kai Cui ◽  
Zhong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Signaling Pathways ◽  
No Production ◽  
Protective Effects ◽  
Prostate Cell ◽  
Coculture System ◽  
Cox 2 ◽  
Tgf Β1

Objective. The aim of the present study was to investigate the protective effects and mechanisms of KLK1 on aging-related prostate alterations and search clues about the application of KLK1 to the treatment of human BPH. Methods. Thirty-six rats including 26 male wild-type SD rats and 10 transgenic rats were fed to 3- or 18-month-old and divided into three groups: young WTR (yWTR) as the control ( n = 16 ), aged WTR (aWTR) ( n = 10 ), and aged TGR (aTGR) ( n = 10 ). The prostates of the three groups of rats (10 rats per group) were harvested to evaluate the levels of KLK1 expression, oxidative stress, fibrosis, and involved signaling pathways, such as NO/cGMP, COX-2/PTGIS/cAMP, and TGF-β1/RhoA/ROCK1, via quantitative PCR, Western blot, histological examinations, and ELISA. Moreover, the remaining 6 yWTRs were sacrificed to obtain primary prostate fibroblast and aortic endothelial cells, and a coculture system was built with the cells for the verification of above signaling pathways in vitro. And the direct effects of bradykinin on prostate cells were detected by MTT experiment. Prostate specimens of 47 patients (age from 48 to 92 years) undergoing BPH surgery were collected after approval. Histological examinations and KLK1 IHC were preformed to analyze the relationship between KLK1 expression and age and prostate fibrosis. Results. The human KLK1 gene only existed and was expressed in aTGR. The prostate of young rats expressed more KLK1 than the aged and the expression of KLK1 in prostate decreased with age in humans ( r = − 0.347 , P = 0.018 ). Compared to the aWTR group, the yWTR and aTGR groups showed milder fibrosis, less oxidative stress, upregulated NO/cGMP, and COX-2/PTGIS/cAMP signaling pathways and inhibited TGF-β1/RhoA/ROCK1 signaling pathway. In the coculture system, KLK1 suppressed TGF-β1-mediated fibroblast-to-myofibroblast transdifferentiation via cleaving LMWK to produce the BK which upregulate eNOS expression and NO production in endothelial cells. BK not only slightly stimulated the proliferation ability of prostatic stromal cells but also upregulated iNOS and inhibited TGF-β1 expression in them. Conclusion. KLK1 protects prostate from oxidative stress and fibrosis via amplified NO/cGMP signal in aged rats. The decrease of KLK1 expression with aging is laying the groundwork for the application of KLK1 to the treatment of human BPH. The current experimental data showed that the side effects of KLK1 on the prostate cell were not obvious.

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