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Halfon M, Emsley R, Agius T, Lyon A, Déglise S, Pascual M, Uygun K, Yeh H, Riella LV, Markmann JF, Bochud PY, Golshayan D, Longchamp A. Association of Kidney Graft Long-term Outcome With Recipient Cystathionine Gamma-lyase Polymorphisms and Hydrogen Sulfide Levels: A Cohort Study. Transplant Direct 2025; 11:e1779. [PMID: 40256682 PMCID: PMC12007866 DOI: 10.1097/txd.0000000000001779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/08/2025] [Accepted: 01/12/2025] [Indexed: 04/22/2025] Open
Abstract
Background Hydrogen sulfide (H2S) produced endogenously by the CTH gene-encoded cystathionine gamma-lyase protects from renal ischemia-reperfusion injury in preclinical models. Here, we hypothesized that CTH gene polymorphisms (single nucleotide polymorphism [SNP]) and recipient H2S serum levels influence kidney graft outcomes after transplantation. Methods We included all consecutive recipients of a first kidney transplant in the Swiss Transplant Cohort Study and with available genotyping. In addition, 192 deceased-donor kidney transplant recipients were randomly selected to measure baseline serum H2S levels. The primary endpoint was graft loss during follow-up. Results CTH SNPs were identified in up to 50% of the patients. During median follow-up (6.4 y, interquartile range: 3.9-9.8), graft loss was observed in 247 (9.8%) of 2518 patients. The incidence of graft loss was associated with the presence or absence of CTH SNPs. Specifically, rs672203 and rs10458561, increased the risk of graft loss (hazard ratio [HR]: 1.36, 95% confidence interval [CI]: 1.04-1.78, P = 0.02; and HR: 1.29, 95% CI: 1.0-1.66, P = 0.05; respectively), whereas rs113285275 was protective (HR: 0.78, 95% CI: 0.6-1.01, P = 0.05). Interestingly, rs672203 was associated with an increased risk of acute rejection (P = 0.05), whereas rs113285275 was associated with a lower risk of acute rejection (P = 0.01). Finally, in patients with delayed graft function, serum H2S levels correlated with lower graft dysfunction (defined as estimated glomerular filtration rate <30 mL/min/1.73 m2) (P = 0.05). Conclusions Graft outcome after kidney transplantation was associated with CTH genotype and, to some extent, H2S serum levels. Further research is needed to define the underlying protective mechanisms.
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Affiliation(s)
- Matthieu Halfon
- Department of Medicine and Surgery, Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Raffaella Emsley
- Service of Vascular Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thomas Agius
- Service of Vascular Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Arnaud Lyon
- Department of Medicine and Surgery, Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Sébastien Déglise
- Service of Vascular Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Manuel Pascual
- Department of Medicine and Surgery, Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Korkut Uygun
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Heidi Yeh
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Leonardo V. Riella
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - James F. Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
| | - Pierre-Yves Bochud
- Department of Medicine, Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Dela Golshayan
- Department of Medicine and Surgery, Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Alban Longchamp
- Service of Vascular Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA
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Gong M, Jiang R, He X, Gu J. Unveiling the link between oversizing ratio and neointimal hyperplasia in a porcine model. Sci Rep 2025; 15:10323. [PMID: 40133361 PMCID: PMC11937583 DOI: 10.1038/s41598-025-88585-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/29/2025] [Indexed: 03/27/2025] Open
Abstract
Intimal hyperplasia (IH) is a major risk for inferior vena cava (IVC) filter retrieval failures and potentially fatal vascular trauma to the IVC or caudal vena cava (CVC) wall post-retrieval. However, demonstrating neointimal formation in humans presents challenges due to the difficulty in obtaining quantitative pathological evidence from the IVC. Here, it was hypothesized that the mismatch between the diameter of the CVC and the filter would correlate with increased IH. Radial force (RF) exerted by filter struts at various CVC diameters was tested in vitro. In vivo, Bama miniature swine were randomly fitted with IVC filters of 32 mm-20 mm diameter, and a three-dimensional digital subtraction angiography model was used to determine the oversizing ratio (OR). After dwelling times of 2, 3, and 4 weeks, the macroscopic CVC wall and intima in the areas adjacent to IVC filter struts were observed. The proliferation and thickness of IH and presentations of vascular smooth muscle cells (VSMCs) were evaluated. Masson trichrome staining was used to determine the production of collagen fiber. The RFs of the IVC filter consistently increased with the OR, suggesting a correlation coefficient (R2 = 0.74, p < 0.001). Notable response in the CVC wall after filter placement, characterized by vessel wall injury, VSMCs dedifferentiation, proliferation, and extracellular matrix secretion, which tended to increase and change over time. Increased ORs and dwelling time correlated linearly with greater IH thickness (adjusted R2 = 0.456, p < 0.001). Moreover, restricted cubic splines (RCS) analysis revealed that ORs had a non-linear relationship with the IH thickness after adjusting for the IVC filter dwelling time (nonlinear p = 0.047, p < 0.001). A linear correlation was also noted between increased ORs and dwelling time with the collagen area fraction (adjusted R2 = 0.860, p < 0.001). Furthermore, RCS indicated a consistently higher risk of increased collagen fiber content when the OR exceeded 100.75% (nonlinear p = 0.047, p < 0.001). IH developed in response to CVC injury, VSMCs proliferation, and secretion of the extracellular matrix collagen fiber. RFs increased with increased ORs. Increased ORs and dwelling time correlate linearly with greater IH thickness and increased production of collagen fiber.
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Affiliation(s)
- Maofeng Gong
- Department of Interventional and Vascular Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Rui Jiang
- Department of Interventional and Vascular Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Xu He
- Department of Interventional and Vascular Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Jianping Gu
- Department of Interventional and Vascular Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, People's Republic of China.
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Mahmood NN, Rashid BM, Abdulla SK, Marouf BH, Hamaamin KS, Othman HH. Effects of Zofenopril and Thymoquinone in Cyclophosphamide-Induced Urotoxicity and Nephrotoxicity in Rats; The Value of Their Anti-Inflammatory and Antioxidant Properties. J Inflamm Res 2025; 18:3657-3676. [PMID: 40093946 PMCID: PMC11910925 DOI: 10.2147/jir.s500375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 03/02/2025] [Indexed: 03/19/2025] Open
Abstract
Objective The study aimed to investigate whether zofenopril (ZOF), thymoquinone (TQ), or their co-administration effectively ameliorates urotoxicity and nephrotoxicity following cyclophosphamide (CPH) treatment. Methods A total of 48 Wister Albino female rats were divided into six groups each of eight rats; negative control (NC), positive control (PC), mesna (MS), ZOF, TQ, and ZOF+TQ groups. Normal saline, mesna, ZOF-15mg/kg, TQ-80mg/kg, and their combination were given orally for 19 days to the groups NC, MS, ZOF, TQ, and ZOF+TQ respectively. On the 17th day, a single dose of CPH 200 mg/kg was given intraperitoneally for all the groups except the NC group. Urine was collected over 24 hours before animal scarification for urinalysis. After scarification, blood, and kidney tissue were obtained for assessment of conventional kidney function parameters, novel kidney injury biomarkers, pro-inflammatory cytokines, oxidative status, complete blood count (CBC), and histopathological examination. Results CPH disturbed the urinary excretion of urea, creatinine, and protein, and significantly elevated novel biomarkers for kidney injury including cystatin-C (Cys-C) (p=0.019) and markedly kidney injury molecule-1 (KIM-1) (p=0.27), the semiquantitative measurement of hematuria revealed significant elevation of hematuria score (p=0.0002), urine pus and protein (p=0.0005). Additionally, CBC-derived inflammatory biomarkers including neutrophil-lymphocyte ratio (NLR) (p=0.001), neutrophil-monocyte ratio (NMR) (p=0.0004), pro-inflammatory cytokine interleukin (IL)-6 (p=0.016) and tumor necrosis factor (TNF)-α (p<=0.007), total antioxidant capacity (TAC) (p<0.0001) were significantly increased. Evidence of obvious histopathological structural alteration was noticed in kidney tissue and bladder urothelium in CPH-treated animals. ZOF, TQ, and their co-treatment significantly prevented these deleterious effects associated with CPH treatment. Conclusion This study demonstrated that ZOF and TQ provided uroprotective and nephroprotective effects against CPH-induced nephrotoxicity by reducing kidney injury biomarkers, and CBC-derived inflammatory markers, restoring antioxidant capacity, and improving histopathological outcomes. The suggested mechanism involves the anti-inflammatory and antioxidant activity of TQ and the sulfhydryl-angiotensin converting enzyme inhibitor ZOF.
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Affiliation(s)
- Neveen Nawzad Mahmood
- Department of Basic Sciences-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
| | - Ban Mousa Rashid
- Department of Basic Sciences-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
| | - Sakar Karem Abdulla
- Department of Basic Sciences-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
| | - Bushra Hassan Marouf
- Department of Pharmacology and Toxicology-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
| | - Karmand Salih Hamaamin
- Department of Pharmacology and Toxicology-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
| | - Hemn Hassan Othman
- Department of Basic Sciences-College of Pharmacy, University of Sulaimani, Sulaimani-Kurdistan Region, Iraq
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Joniová J, Gregor A, Lambelet M, Déglise S, Allagnat F, Wagnières G. Optimizing Photobiomodulation Radiometric and Spectral Parameters In Vitro to Enhance Angiogenesis and Mitochondrial Function. Int J Mol Sci 2024; 26:93. [PMID: 39795951 PMCID: PMC11720580 DOI: 10.3390/ijms26010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Photobiomodulation (PBM) therapy, a therapeutic approach utilizing low-level light, has garnered significant attention for its potential to modulate various biological processes. This study aimed at optimizing and investigating the effects of PBM on angiogenesis and mitochondrial metabolic activity. In vitro experiments using human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) were performed to assess PBM's impacts on cell migration, proliferation, endogenous protoporphyrin IX production, mitochondrial membrane potential, Rhodamine 123 fluorescence lifetime, mitochondrial morphology, and oxygen consumption. Our findings demonstrated that the PBM approach significantly stimulates HUVECs and VSMCs, highlighting the importance of precise light dosimetry for optimal outcomes. Interestingly, our results indicate that in our conditions, the optimal radiometric and spectral parameters are similar for HUVECs and VSMCs for the different endpoints mentioned above. In conclusion, our study strongly suggests that PBM holds promise as a therapeutic intervention for conditions characterized by impaired angiogenesis, such as wound healing, ischemia, and cardiovascular disease. Further research is necessary to fully elucidate the underlying mechanisms and optimize the radiometric and spectral parameters for clinical applications.
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MESH Headings
- Humans
- Mitochondria/metabolism
- Mitochondria/radiation effects
- Human Umbilical Vein Endothelial Cells/radiation effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Low-Level Light Therapy/methods
- Membrane Potential, Mitochondrial/radiation effects
- Neovascularization, Physiologic/radiation effects
- Cell Proliferation/radiation effects
- Cell Movement/radiation effects
- Myocytes, Smooth Muscle/radiation effects
- Myocytes, Smooth Muscle/metabolism
- Muscle, Smooth, Vascular/radiation effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Oxygen Consumption/radiation effects
- Protoporphyrins/metabolism
- Cells, Cultured
- Angiogenesis
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Affiliation(s)
- Jaroslava Joniová
- Laboratory for Functional and Metabolic Imaging (LIFMET), Institute of Physics, Swiss Federal Institute of Technology (EPFL), Station 3, 1015 Lausanne, Switzerland (G.W.)
| | - Aurélien Gregor
- Laboratory for Functional and Metabolic Imaging (LIFMET), Institute of Physics, Swiss Federal Institute of Technology (EPFL), Station 3, 1015 Lausanne, Switzerland (G.W.)
| | - Martine Lambelet
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), 1005 Lausanne, Switzerland; (M.L.); (F.A.)
| | - Sébastien Déglise
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), 1005 Lausanne, Switzerland; (M.L.); (F.A.)
| | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital (CHUV), 1005 Lausanne, Switzerland; (M.L.); (F.A.)
| | - Georges Wagnières
- Laboratory for Functional and Metabolic Imaging (LIFMET), Institute of Physics, Swiss Federal Institute of Technology (EPFL), Station 3, 1015 Lausanne, Switzerland (G.W.)
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Wang C, Chen J, Feng Z, Jian B, Huang S, Feng K, Liu H, Zhou Z, Ye Z, Lu J, Liang M, Wu Z. Fhl1, a new spatially specific protein, regulates vein graft neointimal hyperplasia. Clin Transl Med 2024; 14:e70115. [PMID: 39639552 PMCID: PMC11621235 DOI: 10.1002/ctm2.70115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/04/2024] [Accepted: 11/17/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Vein grafts are commonly employed in revascularisation surgery for multivessel coronary artery disease, yet neointimal hyperplasia (NIH) remains a critical impediment to the long-term patency of these grafts. Despite this, effective methods to precisely identify and target interventions for the neointima are still inadequate. METHODS In this study, Sprague-Dawley (SD) rats were used to establish an external jugular vein transplantation model, and the NIH pathophysiological process was tracked across 11 time points (0-35 days) using various histological stains. Spatial transcriptomics was performed on normal veins and 19-day grafts to explore gene expression in neointimal regions. Immunohistochemical analysis identified neointima-specific markers, while NIH progression was assessed in SD rats with four and a half LIM domains protein 1 (Fhl1) knockout and in human saphenous veins (HSV) with adenovirus-mediated Fhl1 overexpression. RESULTS Typical neointimal formation commenced by day 11 postgrafting and peaked at day 19. Neointimal cells originated from newly generated α-SMA(+) repair cells located outside the grafted vein, displaying a hybrid fibroblast-smooth muscle cell phenotype. Spatial transcriptomics identified stable and sustained Fhl1 expression within the neointima throughout the entire NIH phase. Systemic knockout of Fhl1 in SD rats via the phosphoinositide 3-kinase pathway exacerbated graft inflammation, heightened cell proliferation, and accelerated NIH. Conversely, FHL1 overexpression in cultured HSV suppressed NIH. CONCLUSION These findings indicate that, following grafting into the arterial system, the newly formed repair cells external to the grafted vein play a pivotal role in NIH, with neointimal cells exhibiting stable and continuous Fhl1 expression. Fhl1 serves as a protective factor against NIH both in vivo and in HSV, likely due to its anti-inflammatory and anti-proliferative effects. KEY POINTS This study firstly used spatial transcriptomics technique to analyse the neointima and generated a specific neointimal transcriptomic atlas. Fhl1 exhibits specific and stable expression in the spatial region of the neointima. It has thus far the highest enrichment of expression in the neointima in NIH phases, suggesting that it is a prominent molecular biomarker of neointima. We generated rats with a Fhl1 deletion and found that insufficient Fhl1 expression caused an increase in the severity of vascular inflammation and proliferation during neointimal hyperplasia. Adenovirus-mediated FHL1 overexpression in human saphenous vein have beneficial effects in preventing neointimal hyperplasia. These highlight its potential as a therapeutic target for mitigating vein graft failure associated with cardiovascular procedures. Spatial transcriptomics profiles and morphological observations demonstrated that a newly generated cell population outside the grafted vein with hybrid phenotype between SMCs and fibroblasts contributes to neointimal formation.
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Affiliation(s)
- Chaoqun Wang
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jiantao Chen
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Zicong Feng
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Bohao Jian
- NHC Key Laboratory of Assisted CirculationSun Yat‐Sen UniversityGuangzhouChina
| | - Suiqing Huang
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Kangni Feng
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Haoliang Liu
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Zhuoming Zhou
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Ziyin Ye
- Department of PathologyFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jing Lu
- School of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhouChina
| | - Mengya Liang
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Zhongkai Wu
- Department of Cardiac SurgeryFirst Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
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Palić B, Brizić I, Sher EK, Cvetković I, Džidić-Krivić A, Abdelghani HTM, Sher F. Effects of Zofenopril on Arterial Stiffness in Hypertension Patients. Mol Biotechnol 2023:10.1007/s12033-023-00861-5. [PMID: 37702881 DOI: 10.1007/s12033-023-00861-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/29/2023] [Indexed: 09/14/2023]
Abstract
Angiotensin-converting enzyme inhibitors (ACEIs) reduce arterial stiffness beyond their antihypertensive effect. Studies showed that sulfhydryl ACEIs have the antioxidative potential to improve endothelial function, which might have a clinical effect on arterial distensibility. However, there are no studies that directly compare the effects of sulfhydryl (zofenopril) and non-sulfhydryl ACEIs (enalapril) on arterial stiffness. Therefore, this prospective study aims to compare the effects of enalapril and zofenopril on arterial stiffness and oxidative stress in both short- and long-term treatment of arterial hypertension (AH). Baseline and post-treatment peripheral and central arterial pressure indices, augmentation index (Aix), aortic pulse wave velocity (ao-PWV), serum levels of oxidized low-density cholesterol lipoprotein, LDL and uric acid (UA) were measured. The results showed that acute treatment with zofenopril, in contrast to enalapril, significantly decreased peripheral and central Aix (p < 0.001). Chronic treatment with zofenopril showed a superior effect over enalapril on the reduction of the peripheral systolic arterial pressure with reduction of ao-PWV (p = 0.004), as well as a reduction in peripheral Aix (p = 0.021) and central Aix (p = 0.021). Therefore, this study indicates that zofenopril has beneficial effects on the reduction of arterial stiffness compared to enalapril. It has potent clinical efficacy in AH treatment and further studies should compare its safety and long-term efficacy to other AH drugs that would aid clinicians in treating AH and other various cardiovascular diseases that have arterial stiffness as a common denominator.
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Affiliation(s)
- Benjamin Palić
- Department of Internal Medicine, University Clinical Hospital Mostar, 88000, Mostar, Bosnia and Herzegovina
| | - Ivica Brizić
- Department of Internal Medicine, University Clinical Hospital Mostar, 88000, Mostar, Bosnia and Herzegovina
| | - Emina Karahmet Sher
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK.
| | - Ivona Cvetković
- Department of Laboratory Diagnostics, University Clinical Hospital Mostar, 88000, Mostar, Bosnia and Herzegovina
| | - Amina Džidić-Krivić
- Department of Neurology, Cantonal Hospital Zenica, 72000, Zenica, Bosnia and Herzegovina
- International Society of Engineering Science and Technology, Nottingham, UK
| | - Heba Taha Mohmmed Abdelghani
- Department of Physiology of Physical Activity, College of Sport Sciences and Physical Activity, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Farooq Sher
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK.
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Zhao S, Deslarzes-Dubuis C, Urfer S, Lambelet M, Déglise S, Allagnat F. Cystathionine Gamma Lyase Is Regulated by Flow and Controls Smooth Muscle Migration in Human Saphenous Vein. Antioxidants (Basel) 2023; 12:1731. [PMID: 37760034 PMCID: PMC10525225 DOI: 10.3390/antiox12091731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/28/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The saphenous vein is the conduit of choice for bypass grafting. Unfortunately, the hemodynamic stress associated with the arterial environment of the bypass vein graft leads to the development of intimal hyperplasia (IH), an excessive cellular growth and collagen deposition that results in restenosis and secondary graft occlusion. Hydrogen sulfide (H2S) is a ubiquitous redox-modifying gasotransmitter that inhibits IH. H2S is produced via the reverse trans-sulfuration pathway by three enzymes: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). However, the expression and regulation of these enzymes in the human vasculature remains unclear. Here, we investigated the expression of CSE, CBS and 3-MST in segments of native human saphenous vein and large arteries. Furthermore, we evaluated the regulation of these enzymes in vein segments cultured under static, venous (7 mmHg pressure) or arterial (100 mmHg pressure) pressure. CSE was expressed in the media, neointima and intima of the vessels and was negatively regulated by arterial shear stress. Adenoviral-mediated CSE overexpression or RNA interference-mediated CSE knock-down revealed that CSE inhibited primary human VSMC migration but not proliferation. We propose that high shear stress in arteriovenous bypass grafts inhibits CSE expression in both the media and endothelium, which may contribute to increased VSMC migration in the context of IH.
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Bechelli C, Macabrey D, Deglise S, Allagnat F. Clinical Potential of Hydrogen Sulfide in Peripheral Arterial Disease. Int J Mol Sci 2023; 24:9955. [PMID: 37373103 DOI: 10.3390/ijms24129955] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/01/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Peripheral artery disease (PAD) affects more than 230 million people worldwide. PAD patients suffer from reduced quality of life and are at increased risk of vascular complications and all-cause mortality. Despite its prevalence, impact on quality of life and poor long-term clinical outcomes, PAD remains underdiagnosed and undertreated compared to myocardial infarction and stroke. PAD is due to a combination of macrovascular atherosclerosis and calcification, combined with microvascular rarefaction, leading to chronic peripheral ischemia. Novel therapies are needed to address the increasing incidence of PAD and its difficult long-term pharmacological and surgical management. The cysteine-derived gasotransmitter hydrogen sulfide (H2S) has interesting vasorelaxant, cytoprotective, antioxidant and anti-inflammatory properties. In this review, we describe the current understanding of PAD pathophysiology and the remarkable benefits of H2S against atherosclerosis, inflammation, vascular calcification, and other vasculo-protective effects.
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Affiliation(s)
- Clémence Bechelli
- Department of Vascular Surgery, Lausanne University Hospital, 1005 Lausanne, Switzerland
| | - Diane Macabrey
- Department of Vascular Surgery, Lausanne University Hospital, 1005 Lausanne, Switzerland
| | - Sebastien Deglise
- Department of Vascular Surgery, Lausanne University Hospital, 1005 Lausanne, Switzerland
| | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital, 1005 Lausanne, Switzerland
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Déglise S, Bechelli C, Allagnat F. Vascular smooth muscle cells in intimal hyperplasia, an update. Front Physiol 2023; 13:1081881. [PMID: 36685215 PMCID: PMC9845604 DOI: 10.3389/fphys.2022.1081881] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/12/2022] [Indexed: 01/05/2023] Open
Abstract
Arterial occlusive disease is the leading cause of death in Western countries. Core contemporary therapies for this disease include angioplasties, stents, endarterectomies and bypass surgery. However, these treatments suffer from high failure rates due to re-occlusive vascular wall adaptations and restenosis. Restenosis following vascular surgery is largely due to intimal hyperplasia. Intimal hyperplasia develops in response to vessel injury, leading to inflammation, vascular smooth muscle cells dedifferentiation, migration, proliferation and secretion of extra-cellular matrix into the vessel's innermost layer or intima. In this review, we describe the current state of knowledge on the origin and mechanisms underlying the dysregulated proliferation of vascular smooth muscle cells in intimal hyperplasia, and we present the new avenues of research targeting VSMC phenotype and proliferation.
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Affiliation(s)
| | | | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
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10
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Zheng W, Tian E, Liu Z, Zhou C, Yang P, Tian K, Liao W, Li J, Ren C. Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective. Front Pharmacol 2022; 13:968104. [PMID: 36386190 PMCID: PMC9664202 DOI: 10.3389/fphar.2022.968104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 10/17/2022] [Indexed: 10/07/2023] Open
Abstract
Angiotensin-converting enzyme (ACE), a zinc metalloprotein, is a central component of the renin-angiotensin system (RAS). It degrades bradykinin and other vasoactive peptides. Angiotensin-converting-enzyme inhibitors (ACE inhibitors, ACEIs) decrease the formation of angiotensin II and increase the level of bradykinin, thus relaxing blood vessels as well as reducing blood volume, lowering blood pressure and reducing oxygen consumption by the heart, which can be used to prevent and treat cardiovascular diseases and kidney diseases. Nevertheless, ACEIs are associated with a range of adverse effects such as renal insufficiency, which limits their use. In recent years, researchers have attempted to reduce the adverse effects of ACEIs by improving the selectivity of ACEIs for structural domains based on conformational relationships, and have developed a series of novel ACEIs. In this review, we have summarized the research advances of ACE inhibitors, focusing on the development sources, design strategies and analysis of structure-activity relationships and the biological activities of ACE inhibitors.
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Affiliation(s)
- Wenyue Zheng
- Departments of Obstetrics & Gynecology and Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Health Management Center, West China Second University Hospital, Chengdu, China
| | - Erkang Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhen Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Changhan Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Pei Yang
- Departments of Obstetrics & Gynecology and Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Health Management Center, West China Second University Hospital, Chengdu, China
| | - Keyue Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wen Liao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Juan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu, China
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11
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Macabrey D, Joniová J, Gasser Q, Bechelli C, Longchamp A, Urfer S, Lambelet M, Fu CY, Schwarz G, Wagnières G, Déglise S, Allagnat F. Sodium thiosulfate, a source of hydrogen sulfide, stimulates endothelial cell proliferation and neovascularization. Front Cardiovasc Med 2022; 9:965965. [PMID: 36262202 PMCID: PMC9575962 DOI: 10.3389/fcvm.2022.965965] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Therapies to accelerate vascular repair are currently lacking. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, promotes angiogenesis. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would stimulate angiogenesis and vascular repair. STS stimulated neovascularization in WT and LDLR receptor knockout mice following hindlimb ischemia as evidenced by increased leg perfusion assessed by laser Doppler imaging, and capillary density in the gastrocnemius muscle. STS also promoted VEGF-dependent angiogenesis in matrigel plugs in vivo and in the chorioallantoic membrane of chick embryos. In vitro, STS and NaHS stimulated human umbilical vein endothelial cell (HUVEC) migration and proliferation. Seahorse experiments further revealed that STS inhibited mitochondrial respiration and promoted glycolysis in HUVEC. The effect of STS on migration and proliferation was glycolysis-dependent. STS probably acts through metabolic reprogramming of endothelial cells toward a more proliferative glycolytic state. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases.
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Affiliation(s)
- Diane Macabrey
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Jaroslava Joniová
- Laboratory for Functional and Metabolic Imaging, LIFMET, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Quentin Gasser
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Clémence Bechelli
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Alban Longchamp
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Severine Urfer
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Martine Lambelet
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Chun-Yu Fu
- Institute of Biochemistry, Department of Chemistry & Center for Molecular Medicine, Cologne University, Cologne, Germany
| | - Guenter Schwarz
- Institute of Biochemistry, Department of Chemistry & Center for Molecular Medicine, Cologne University, Cologne, Germany
| | - Georges Wagnières
- Laboratory for Functional and Metabolic Imaging, LIFMET, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Sébastien Déglise
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland,*Correspondence: Florent Allagnat,
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12
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Macabrey D, Longchamp A, Déglise S, Allagnat F. Clinical Use of Hydrogen Sulfide to Protect Against Intimal Hyperplasia. Front Cardiovasc Med 2022; 9:876639. [PMID: 35479275 PMCID: PMC9035533 DOI: 10.3389/fcvm.2022.876639] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/18/2022] [Indexed: 12/27/2022] Open
Abstract
Arterial occlusive disease is the narrowing of the arteries via atherosclerotic plaque buildup. The major risk factors for arterial occlusive disease are age, high levels of cholesterol and triglycerides, diabetes, high blood pressure, and smoking. Arterial occlusive disease is the leading cause of death in Western countries. Patients who suffer from arterial occlusive disease develop peripheral arterial disease (PAD) when the narrowing affects limbs, stroke when the narrowing affects carotid arteries, and heart disease when the narrowing affects coronary arteries. When lifestyle interventions (exercise, diet…) fail, the only solution remains surgical endovascular and open revascularization. Unfortunately, these surgeries still suffer from high failure rates due to re-occlusive vascular wall adaptations, which is largely due to intimal hyperplasia (IH). IH develops in response to vessel injury, leading to inflammation, vascular smooth muscle cells dedifferentiation, migration, proliferation and secretion of extra-cellular matrix into the vessel’s innermost layer or intima. Re-occlusive IH lesions result in costly and complex recurrent end-organ ischemia, and often lead to loss of limb, brain function, or life. Despite decades of IH research, limited therapies are currently available. Hydrogen sulfide (H2S) is an endogenous gasotransmitter derived from cysteine metabolism. Although environmental exposure to exogenous high H2S is toxic, endogenous H2S has important vasorelaxant, cytoprotective and anti-inflammatory properties. Its vasculo-protective properties have attracted a remarkable amount of attention, especially its ability to inhibit IH. This review summarizes IH pathophysiology and treatment, and provides an overview of the potential clinical role of H2S to prevent IH and restenosis.
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Affiliation(s)
- Diane Macabrey
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Alban Longchamp
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Sébastien Déglise
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Florent Allagnat
- Department of Vascular Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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13
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Desai M. Can Zofenopril Be the Answer to the Achilles Heel of Vascular Surgery? Eur J Vasc Endovasc Surg 2021; 63:347. [PMID: 34686451 DOI: 10.1016/j.ejvs.2021.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/07/2021] [Accepted: 09/11/2021] [Indexed: 11/03/2022]
Affiliation(s)
- Mital Desai
- St George's Vascular Institute, St George's University Hospitals NHS Foundation Trust, London, UK; St George's University of London, London, UK.
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