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Thakur MR, Tupe RS. l-Arginine: A multifaceted regulator of diabetic cardiomyopathy. Biochem Biophys Res Commun 2025; 761:151720. [PMID: 40186920 DOI: 10.1016/j.bbrc.2025.151720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
In diabetes mellitus, dysregulated glucose and lipid metabolism lead to diabetic cardiomyopathy (DCM) by imparting pathological myocardial remodeling and cellular injury. Accelerated glycation, oxidative stress, and activated inflammatory pathways culminate in cardiac fibrosis and hypertrophy in DCM. The regulatory effects of l-Arginine (L-Arg) have been elucidated in the pathological changes of DCM, including myocardial fibrosis, hypertrophy, and apoptosis, by inhibiting glycation and oxidative stress-induced inflammation. Disturbed L-Arg metabolism and decreased intracellular L-Arg pool are correlated with the progression of DCM; therefore, L-Arg supplementation has been prescribed for various cardiovascular dysfunctions. This review expands the therapeutic potential of L-Arg supplementation in DCM by elucidating its molecular mechanism of action and exploring potential clinical outcomes.
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Affiliation(s)
- Muskan R Thakur
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, 412115, Maharashtra, India
| | - Rashmi S Tupe
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune, 412115, Maharashtra, India.
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2
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Zhao S, Yu H, Li Z, Chen W, Liu K, Dai H, Wang G, Zhang Z, Xie J, He Y, Li L. Single-cell RNA sequencing reveals a new mechanism of endothelial cell heterogeneity and healing in diabetic foot ulcers. Biol Direct 2025; 20:34. [PMID: 40121493 PMCID: PMC11929994 DOI: 10.1186/s13062-025-00628-9] [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: 01/11/2025] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Diabetic foot ulcers (DFU) are a common and severe complication among diabetic patients, posing a significant burden on patients' quality of life and healthcare systems due to their high incidence, amputation rates, and mortality. This study utilized single-cell RNA sequencing technology to deeply analyze the cellular heterogeneity of the skin on the feet ofDFU patients and the transcriptomic characteristics of endothelial cells, aiming to identify key cell populations and genes associated with the healing and progression of DFU. The study found that endothelial cells from DFU patients exhibited significant transcriptomic differences under various conditions, particularly in signaling pathways related to inflammatory responses and angiogenesis. Through trajectory analysis and cell communication research, we revealed the key role of endothelial cell subsets in the development of DFU and identified multiple important gene modules associated with the progression of DFU. Notably, the promoting effect of the SH3BGRL3 gene on endothelial cell proliferation, migration, and angiogenic capabilities under high glucose conditions was experimentally verified, providing a new potential target and theoretical basis for the treatment of DFU. This study not only enhances the understanding of the pathogenesis ofDFU but also provides a scientific basis for the development ofnew therapeutic strategies.
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Affiliation(s)
- Songyun Zhao
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hua Yu
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zihao Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wanying Chen
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kaibo Liu
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hao Dai
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gaoyi Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zibing Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiaheng Xie
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China.
| | - Yucang He
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Liqun Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- National Key Clinical Specialty (Wound Healing), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Ding Z, Yang C, Zhai X, Xia Y, Liu J, Yu M. Polyethylene Glycol Loxenatide Accelerates Diabetic Wound Healing by Downregulating Systemic Inflammation and Improving Endothelial Progenitor Cell Functions. Int J Mol Sci 2025; 26:2367. [PMID: 40076985 PMCID: PMC11901084 DOI: 10.3390/ijms26052367] [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: 02/08/2025] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Diabetes wound healing presents several significant challenges, which can complicate recovery and lead to severe consequences. Polyethylene glycol loxenatide (PEG-loxe), a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), shows cardiovascular benefits, yet its role in diabetic wound healing remains unclear. Diabetic mice received PEG-loxe (0.03 mg/kg/week, i.p.) for three months. Glucose metabolism was evaluated using the insulin tolerance test (ITT) and oral glucose tolerance test (OGTT). Wound closure rates and angiogenesis-related proteins were analyzed. Serum proteomics was performed using the Olink assay to evaluate systemic inflammation. In vitro, human endothelial progenitor cells (EPCs) were exposed to high glucose and palmitic acid, with or without PEG-loxe treatment. EPC tube formation and migratory capacity were evaluated using the tube formation assay and migration assay, respectively. Levels of nitric oxide (NO) and phosphorylated endothelial nitric oxide synthase (p-eNOS) were quantified. Mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential were assessed using MitoSOX and JC-1 staining. Cellular respiratory function was analyzed via the Seahorse XF assay. Autophagy was evaluated by examining the expression of autophagy-related proteins and the colocalization of mitochondria with lysosomes. PEG-loxe improved glucose tolerance, accelerated wound closure, and upregulated the hypoxia-inducible factor-1α/vascular endothelial growth factor/stromal cell-derived factor-1 axis (HIF-1α/VEGF/SDF-1) in diabetic mice. Serum proteomics revealed reduced pro-inflammatory markers and elevated anti-inflammatory IL-5. In vitro, PEG-loxe restored EPC function by enhancing NO production, reducing mitochondrial ROS, improving cellular respiratory function, and restoring autophagic flux. These findings suggest that PEG-loxe offers therapeutic benefits for diabetic wound healing by downregulating systemic inflammation, enhancing angiogenesis, and improving mitochondrial quality control in EPCs, highlighting GLP-1RAs as potential therapies for diabetic vascular complications.
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Affiliation(s)
- Zerui Ding
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
| | - Chunru Yang
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
| | - Xiaojun Zhai
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
| | - Yuqi Xia
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
| | - Jieying Liu
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
- Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Miao Yu
- Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Z.D.); (C.Y.)
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4
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Pandolfi S, Chirumbolo S, Franzini M, Tirelli U, Valdenassi L. Oxygen-ozone therapy for myocardial ischemic stroke and cardiovascular disorders. Med Gas Res 2025; 15:36-43. [PMID: 39217427 PMCID: PMC11515079 DOI: 10.4103/mgr.medgasres-d-23-00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/08/2023] [Accepted: 07/10/2024] [Indexed: 09/04/2024] Open
Abstract
Cardiovascular diseases (CVDs) represent a major concern for human health worldwide. Emergencies in this field include wide repertories of studies dealing primarily with CVD prevention. In addition to dietary habits and lifestyles, medical knowledge is fully needed to improve public educational programs toward cardiovascular risk factors and to enrich the endowment of pharmaceutical options and therapies to address CVDs, particularly for ischemic damage due to an impairment in the endothelial-myocardial relationship. Because ozone is a stimulator of the endothelial nitric oxide synthase/nitric oxide pathway, ozone therapy has been widely demonstrated to have the ability to counteract endothelial-cardiac disorders, providing a novel straightforward opportunity to reduce the impact of CVDs, including atrial fibrillation. In this review, we attempt to establish a state-of-the-art method for the use of ozone in CVD, suggesting that future remarks be addressed to provide fundamental insights into this issue. The purpose of this study was to highlight the role of ozone in the adjunctive medical treatment of cardiovascular pathologies such as acute myocardial infarction due to ischemic disorders.
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Affiliation(s)
- Sergio Pandolfi
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
| | - Salvatore Chirumbolo
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Marianno Franzini
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
| | | | - Luigi Valdenassi
- High School Master of Oxygen Ozone Therapy, University of Pavia, Pavia, Italy
- Italian Scientific Society of Oxygen-Ozone Therapy (SIOOT), Gorle, Italy
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Chen Y, Wang H, Yang M, Shen Z, Gao Y. Exploring the Effects of Metformin on the Body via the Urine Proteome. Biomolecules 2025; 15:241. [PMID: 40001544 PMCID: PMC11853151 DOI: 10.3390/biom15020241] [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: 01/05/2025] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Metformin is the first-line medication for treating type 2 diabetes mellitus, with more than 200 million patients taking it daily. Its effects are extensive and play a positive role in multiple areas. Can its effects and potential mechanisms be explored through the urine proteome? In this study, 166 differential proteins were identified following the administration of 150 mg/(kg·d) of metformin to rats for five consecutive days. These included complement component C6, pyruvate kinase, coagulation factor X, growth differentiation factor 15, carboxypeptidase A4, chymotrypsin-like elastase family member 1, and L-lactate dehydrogenase C chain. Several of these proteins have been reported to be directly affected by metformin or associated with its effects. Multiple biological pathways enriched by these differential proteins, or proteins containing differentially modified peptides, have been reported to be associated with metformin, such as the glutathione metabolic process, negative regulation of gluconeogenesis, and the renin-angiotensin system. Additionally, some significantly changed proteins and enriched biological pathways, not yet reported to be associated with metformin's effects, may provide clues for exploring its potential mechanisms. In conclusion, the application of the urine proteome offers a comprehensive and systematic approach to exploring the effects of drugs, providing a new perspective on the study of metformin's mechanisms.
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Affiliation(s)
| | | | | | | | - Youhe Gao
- Gene Engineering Drug and Biotechnology Beijing Key Laboratory, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (Y.C.); (H.W.); (M.Y.); (Z.S.)
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Batori RK, Bordan Z, Padgett CA, Huo Y, Chen F, Atawia RT, Lucas R, Ushio-Fukai M, Fukai T, Belin de Chantemele EJ, Stepp DW, Fulton DJR. PFKFB3 Connects Glycolytic Metabolism with Endothelial Dysfunction in Human and Rodent Obesity. Antioxidants (Basel) 2025; 14:172. [PMID: 40002359 PMCID: PMC11851787 DOI: 10.3390/antiox14020172] [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: 01/07/2025] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
Obesity and type 2 diabetes (T2D) increase cardiovascular risk, largely due to altered metabolic state. An early consequence of T2D/obesity is the loss of endothelial function and impaired nitric oxide (NO) signaling. In blood vessels, endothelial nitric oxide synthase (eNOS) synthesizes NO to maintain vessel homeostasis. The biological actions of NO are compromised by superoxide that is generated by NADPH oxidases (NOXs). Herein we investigated how altered metabolism affects superoxide/NO balance in obesity. We found that eNOS expression and NO bioavailability are significantly decreased in endothelial cells (ECs) from T2D patients and animal models of obesity. In parallel, PFKFB3, a key glycolytic regulatory enzyme, is significantly increased in ECs of obese animals. EC overexpression of wild-type and a cytosol-restricted mutant PFKFB3 decreased NO production due to increased eNOS-T495 phosphorylation. PFKFB3 also blunted Akt-S473 phosphorylation, reducing stimulus-dependent phosphorylation of S1177 and the activation of eNOS. Furthermore, PFKFB3 enhanced the activities of NOX1 and NOX5, which are major contributors to endothelial dysfunction. Prolonged exposure of ECs to high glucose or TNFα, which are hallmarks of T2D, leads to increased PFKFB3 expression. These results demonstrate a novel functional relationship between endothelial metabolism, ROS, and NO balance that may contribute to endothelial dysfunction in obesity.
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Affiliation(s)
- Robert K. Batori
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
| | - Zsuzsanna Bordan
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
| | - Caleb A. Padgett
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
| | - Yuqing Huo
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Feng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing 210029, China;
| | - Reem T. Atawia
- Department of Pharmaceutical Sciences, College of Pharmacy, Southwestern Oklahoma State University, Weatherford, OK 73096, USA;
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Rudolf Lucas
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Masuko Ushio-Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Medicine (Cardiology), Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Tohru Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30912, USA
| | - Eric J. Belin de Chantemele
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Medicine (Cardiology), Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - David W. Stepp
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - David J. R. Fulton
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (R.K.B.); (Z.B.); (C.A.P.); (R.L.); (M.U.-F.); (T.F.); (E.J.B.d.C.); (D.W.S.)
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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Vitale A, De Musis C, Bimonte M, Rubert J, Fogliano V. In vitro cellular model systems provide a promising alternative to animal experiments for studying the intestine-organ axis. Crit Rev Biotechnol 2025:1-18. [PMID: 39848642 DOI: 10.1080/07388551.2025.2452620] [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: 01/05/2024] [Revised: 10/30/2024] [Accepted: 12/17/2024] [Indexed: 01/25/2025]
Abstract
Limiting animal experiments is essential for ethical issues and also because scientific evidence highlights the discrepancies between human and animal metabolism. This review aims to provide a critical discussion of the strengths and limitations of the most appropriate in vitro intestine model to answer complex research questions in pharmaceutical and nutraceutical fields. This review describes the components contributing to the definition of the gut barrier structure, from the outer mucus layer to the inner part of lamina propria, including endothelial and neuronal networks. We conclude that the main advantage of these co-culture models is their versatility since they are modulable systems in which each component can be added, changed, or removed to reproduce a specific physiological condition each time. Additionally, we compare intestinal organoid models and microfluidic systems with well-established co-culture models.
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Affiliation(s)
| | | | | | - Josep Rubert
- Food Quality and Design group, Wageningen University, Wageningen, The Netherlands
| | - Vincenzo Fogliano
- Arterra Biosciences.P.A, Naples, Italy
- Food Quality and Design group, Wageningen University, Wageningen, The Netherlands
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Kots AY, Bian K. Regulation and Pharmacology of the Cyclic GMP and Nitric Oxide Pathway in Embryonic and Adult Stem Cells. Cells 2024; 13:2008. [PMID: 39682756 PMCID: PMC11639989 DOI: 10.3390/cells13232008] [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: 10/31/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
This review summarizes recent advances in understanding the role of the nitric oxide (NO) and cyclic GMP (cGMP) pathway in stem cells. The levels of expression of various components of the pathway are changed during the differentiation of pluripotent embryonic stem cells. In undifferentiated stem cells, NO regulates self-renewal and survival predominantly through cGMP-independent mechanisms. Natriuretic peptides influence the growth of undifferentiated stem cells by activating particulate isoforms of guanylyl cyclases in a cGMP-mediated manner. The differentiation, recruitment, survival, migration, and homing of partially differentiated precursor cells of various types are sensitive to regulation by endogenous levels of NO and natriuretic peptides produced by stem cells, within surrounding tissues, and by the application of various pharmacological agents known to influence the cGMP pathway. Numerous drugs and formulations target various components of the cGMP pathway to influence the therapeutic efficacy of stem cell-based therapies. Thus, pharmacological manipulation of the cGMP pathway in stem cells can be potentially used to develop novel strategies in regenerative medicine.
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Affiliation(s)
- Alexander Y. Kots
- Veteran Affairs Palo Alto Health Care System, US Department of Veteran Affairs, Palo Alto, CA 90304, USA
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Wu D, Zhu P, Shi Z, Li C, Wu C, Sun W, Ran J. Autologous Platelet-Rich Gel Accelerates Diabetic Wound Healing Through Inhibition of Ferritinophagy. INT J LOW EXTR WOUND 2024:15347346241258528. [PMID: 38839257 DOI: 10.1177/15347346241258528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
Aims: The objective was to examine the efficacy of autologous platelet-rich gel (APG) in treating diabetic wound and investigate the association between APG and ferritinophagy. Methods: A total of 32 patients with diabetic foot (DF) and Wagner grade 1 to 2 were included. Within the APG group, individuals with DF received weekly APG treatment. In the non-APG group, DF patients received daily dressing changes. Flow cytometry quantified the proportion of endothelial progenitor cells (EPCs) in peripheral blood on days 0 and 10. The diabetic rat model was induced using Streptozotocin. Two circular skin wounds were created on the backs of rats. The normal glucose group received daily dressing changes on the wound. In the diabetic group, the left wound underwent daily dressing changes, whereas the right wound was treated with APG once a week. CD34 levels were tested 7 days after the skin damage. The levels of glutathione peroxidase 4 (GPX4), Nuclear Receptor Coactivator 4 (NCOA4), Light chain 3 (LC3), and Masson staining were quantified on 14 days. The wound area and wound healing rate were separately measured at 0 and 14 days after the injury, regardless of DF patients or diabetic rats. Results: The wound healing rate was higher in the APG group than in the non-APG group, regardless of DF patients or diabetic rats. The APG group had a greater ΔEPCs% in DF patients than the non-APG group. Regarding rat experiment, the APG group exhibited lower levels of NCOA4, and LC3 expressions and a shorter wound healing time. However, the APG group showed higher levels of CD34 expression, GPX4 protein, and collagen fibers than the non-APG group. Conclusions: Autologous platelet-rich gel accelerated the wound healing rate in diabetic populations and rats. Autologous platelet-rich gel promoted EPCs counts, collagen fiber volume, and vessel numbers. Autologous platelet-rich gel decreased LC3 and NCOA4 expression, but increased GPX4 protein expression. The possible mechanism was the inhibition of ferritinophagy.
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Affiliation(s)
- Daoai Wu
- Department of Endocrinology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, China
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Ping Zhu
- Department of Endocrinology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, China
| | - Zhaoming Shi
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Chen Li
- Department of Blood Transfusion, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Chenchen Wu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Weihua Sun
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Jianmin Ran
- Department of Endocrinology, Guangzhou Red Cross Hospital Affiliated to Jinan University, Guangzhou, China
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10
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Hettinger G, Mitra N, Thom SR, Margolis DJ. An Improved Clinical and Genetics-Based Prediction Model for Diabetic Foot Ulcer Healing. Adv Wound Care (New Rochelle) 2024; 13:281-290. [PMID: 38258807 PMCID: PMC11339549 DOI: 10.1089/wound.2023.0194] [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: 11/27/2023] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
Objective: The goal of this investigation was to use comprehensive prediction modeling tools and available genetic information to try to improve upon the performance of simple clinical models in predicting whether a diabetic foot ulcer (DFU) will heal. Approach: We utilized a cohort study (n = 206) that included clinical factors, measurements of circulating endothelial precursor cells (CEPCs), and fine sequencing of the NOS1AP gene. We derived and selected relevant predictive features from this patient-level information using statistical and machine learning techniques. We then developed prognostic models using machine learning approaches and assessed predictive performance. The presentation is consistent with TRIPOD requirements. Results: Models using baseline clinical and CEPC data had an area under the receiver operating characteristic curve (AUC) of 0.73 (0.66-0.80). Models using only single nucleotide polymorphisms (SNPs) of the NOS1AP gene had an AUC of 0.67 (95% confidence interval, CI: [0.59-0.75]). However, models incorporating baseline and SNP information resulted in improved AUC (0.80, 95% CI [0.73-0.87]). Innovation: We provide a rigorous analysis demonstrating the predictive potential of genetic information in DFU healing. In this process, we present a framework for using advanced statistical and bioinformatics techniques for creating superior prognostic models and identify potentially predictive SNPs for future research. Conclusion: We have developed a new benchmark for which future predictive models can be compared against. Such models will enable wound care experts to more accurately predict whether a patient will heal and aid clinical trialists in designing studies to evaluate therapies for subjects likely or unlikely to heal.
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Affiliation(s)
- Gary Hettinger
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Nandita Mitra
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Stephen R. Thom
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David J. Margolis
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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11
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Di Pietro P, Abate AC, Prete V, Damato A, Venturini E, Rusciano MR, Izzo C, Visco V, Ciccarelli M, Vecchione C, Carrizzo A. C2CD4B Evokes Oxidative Stress and Vascular Dysfunction via a PI3K/Akt/PKCα-Signaling Pathway. Antioxidants (Basel) 2024; 13:101. [PMID: 38247525 PMCID: PMC10812653 DOI: 10.3390/antiox13010101] [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: 11/29/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
High glucose-induced endothelial dysfunction is an important pathological feature of diabetic vasculopathy. While genome-wide studies have identified an association between type 2 diabetes mellitus (T2DM) and increased expression of a C2 calcium-dependent domain containing 4B (C2CD4B), no study has yet explored the possible direct effect of C2CD4B on vascular function. Vascular reactivity studies were conducted using a pressure myograph, and nitric oxide and oxidative stress were assessed through difluorofluorescein diacetate and dihydroethidium, respectively. We demonstrate that high glucose upregulated both mRNA and protein expression of C2CD4B in mice mesenteric arteries in a time-dependent manner. Notably, the inhibition of C2CD4B expression by genetic knockdown efficiently prevented hyperglycemia-induced oxidative stress, endothelial dysfunction, and loss of nitric oxide (NO) bioavailability. Recombinant C2CD4B evoked endothelial dysfunction of mice mesenteric arteries, an effect associated with increased reactive oxygen species (ROS) and decreased NO production. In isolated human umbilical vein endothelial cells (HUVECs), C2CD4B increased phosphorylation of endothelial nitric oxide synthase (eNOS) at the inhibitory site Thr495 and reduced eNOS dimerization. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and PKCα effectively attenuated oxidative stress, NO reduction, impairment of endothelial function, and eNOS uncoupling induced by C2CD4B. These data demonstrate, for the first time, that C2CD4B exerts a direct effect on vascular endothelium via a phosphoinositide 3-kinase (PI3K)/Akt/PKCα-signaling pathway, providing a new perspective on C2CD4B as a promising therapeutic target for the prevention of oxidative stress in diabetes-induced endothelial dysfunction.
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Affiliation(s)
- Paola Di Pietro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Angela Carmelita Abate
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Valeria Prete
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Antonio Damato
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.D.); (E.V.)
| | - Eleonora Venturini
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.D.); (E.V.)
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Carmine Izzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Valeria Visco
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.D.); (E.V.)
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (P.D.P.); (A.C.A.); (V.P.); (M.R.R.); (C.I.); (V.V.); (M.C.); (C.V.)
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.D.); (E.V.)
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Yang C, Mu Y, Li S, Zhang Y, Liu X, Li J. Tanshinone IIA: a Chinese herbal ingredient for the treatment of atherosclerosis. Front Pharmacol 2023; 14:1321880. [PMID: 38108067 PMCID: PMC10722201 DOI: 10.3389/fphar.2023.1321880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 11/21/2023] [Indexed: 12/19/2023] Open
Abstract
Tanshinone IIA (Tan IIA) is a fat-soluble compound extracted from Salvia miltiorrhiza, which has a protective effect against atherosclerosis (AS). Tan IIA can inhibit oxidative stress and inflammatory damage of vascular endothelial cells (VECs) and improve endothelial cell dysfunction. Tan IIA also has a good protective effect on vascular smooth muscle cells (VSMCs). It can reduce vascular stenosis by inhibiting the proliferation and migration of vascular smooth muscle cells (VSMCs), and improve the stability of the fibrous cap of atherosclerotic plaque by inhibiting apoptosis and inflammation of VSMCs. In addition, Tan IIA inhibits the inflammatory response of macrophages and the formation of foam cells in atherosclerotic plaques. In summary, Tan IIA improves AS through a complex pathway. We propose to further study the specific molecular targets of Tan IIA using systems biology methods, so as to fundamentally elucidate the mechanism of Tan IIA. It is worth mentioning that there is a lack of high-quality evidence-based medical data on Tan IIA treatment of AS. We recommend that a randomized controlled clinical trial be conducted to evaluate the exact efficacy of Tan IIA in improving AS. Finally, sodium tanshinone IIA sulfonate (STS) can cause adverse drug reactions in some patients, which needs our attention.
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Affiliation(s)
- Chunkun Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | | | - Shuanghong Li
- Weifang Hospital of Traditional Chinese Medicine, Weifang, China
| | - Yang Zhang
- Weifang People’s Hospital, Weifang, China
| | - Xiaoyuan Liu
- Weifang Hospital of Traditional Chinese Medicine, Weifang, China
| | - Jun Li
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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13
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Benítez-Camacho J, Ballesteros A, Beltrán-Camacho L, Rojas-Torres M, Rosal-Vela A, Jimenez-Palomares M, Sanchez-Gomar I, Durán-Ruiz MC. Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications. Stem Cell Res Ther 2023; 14:324. [PMID: 37950274 PMCID: PMC10636846 DOI: 10.1186/s13287-023-03537-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/13/2023] [Indexed: 11/12/2023] Open
Abstract
Diabetes mellitus (DM) constitutes a chronic metabolic disease characterized by elevated levels of blood glucose which can also lead to the so-called diabetic vascular complications (DVCs), responsible for most of the morbidity, hospitalizations and death registered in these patients. Currently, different approaches to prevent or reduce DM and its DVCs have focused on reducing blood sugar levels, cholesterol management or even changes in lifestyle habits. However, even the strictest glycaemic control strategies are not always sufficient to prevent the development of DVCs, which reflects the need to identify reliable biomarkers capable of predicting further vascular complications in diabetic patients. Endothelial progenitor cells (EPCs), widely known for their potential applications in cell therapy due to their regenerative properties, may be used as differential markers in DVCs, considering that the number and functionality of these cells are affected under the pathological environments related to DM. Besides, drugs commonly used with DM patients may influence the level or behaviour of EPCs as a pleiotropic effect that could finally be decisive in the prognosis of the disease. In the current review, we have analysed the relationship between diabetes and DVCs, focusing on the potential use of EPCs as biomarkers of diabetes progression towards the development of major vascular complications. Moreover, the effects of different drugs on the number and function of EPCs have been also addressed.
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Affiliation(s)
- Josefa Benítez-Camacho
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Antonio Ballesteros
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
| | - Lucía Beltrán-Camacho
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
- Cell Biology, Physiology and Immunology Department, Córdoba University, Córdoba, Spain
| | - Marta Rojas-Torres
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Antonio Rosal-Vela
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Margarita Jimenez-Palomares
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Ismael Sanchez-Gomar
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Mª Carmen Durán-Ruiz
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain.
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain.
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Sernek B, Kamnikar R, Sebestjen M, Boc A, Boc V. Smoking and Diabetes Attenuate Number of CD34 + Haematopoietic Stem Cells in Peripheral Blood of Patients with Advanced Peripheral Artery Disease. Int J Mol Sci 2023; 24:15346. [PMID: 37895025 PMCID: PMC10607776 DOI: 10.3390/ijms242015346] [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: 09/30/2023] [Revised: 10/15/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Peripheral artery disease (PAD) is a globally prevalent problem with limited treatment options, leaving up to a fifth of patients remediless. The emergence of new studies on cell therapy in recent years offers a new promising option for their treatment. Our aim was to explore how the number of CD34+ hematopoietic cells in the peripheral blood of PAD patients is associated with patients' functional as well as atherogenic factors. We selected 30 patients with advanced PAD, recorded their performance in a walking test in standard conditions and sampled their blood for further analysis with an emphasis on CD34+ cell selection and counting. No correlation of the CD34+ cell number was confirmed with any of the observed laboratory parameters. There was an association between the claudication distance and the number of CD34+ cells (r = -0.403, p = 0.046). The number of CD34+ cells differed between patients with and without type II diabetes (p = 0.071) and between active smokers, past smokers, and non-smokers (p = 0.035; p = 0.068, p = 0.051, respectively), with both smoking and presence of diabetes type II having a negative effect on the number of CD34+ cells. Our study demonstrated a dependence of the CD34+ cell number on the patient's characteristics.
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Affiliation(s)
- Barbara Sernek
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (B.S.); (R.K.); (A.B.)
| | - Rok Kamnikar
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (B.S.); (R.K.); (A.B.)
| | - Miran Sebestjen
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (B.S.); (R.K.); (A.B.)
- Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
- Department of Cardiology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Anja Boc
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (B.S.); (R.K.); (A.B.)
- Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
| | - Vinko Boc
- Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
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Luo JY, Cheng CK, Gou L, He L, Zhao L, Zhang Y, Wang L, Lau CW, Xu A, Chen AF, Huang Y. Induction of KLF2 by Exercise Activates eNOS to Improve Vasodilatation in Diabetic Mice. Diabetes 2023; 72:1330-1342. [PMID: 37347764 DOI: 10.2337/db23-0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 06/13/2023] [Indexed: 06/24/2023]
Abstract
Diabetic endothelial dysfunction associated with diminished endothelial nitric oxide (NO) synthase (eNOS) activity accelerates the development of atherosclerosis and cardiomyopathy. However, the approaches to restore eNOS activity and endothelial function in diabetes remain limited. The current study shows that enhanced expression of Krüppel-like factor 2 (KLF2), a shear stress-inducible transcription factor, effectively improves endothelial function through increasing NO bioavailability. KLF2 expression is suppressed in diabetic mouse aortic endothelium. Running exercise and simvastatin treatment induce endothelial KLF2 expression in db/db mice. Adenovirus-mediated endothelium-specific KLF2 overexpression enhances both endothelium-dependent relaxation and flow-mediated dilatation, while it attenuates oxidative stress in diabetic mouse arteries. KLF2 overexpression increases the phosphorylation of eNOS at serine 1177 and eNOS dimerization. RNA-sequencing analysis reveals that KLF2 transcriptionally upregulates genes that are enriched in the cyclic guanosine monophosphate-protein kinase G-signaling pathway, cAMP-signaling pathway, and insulin-signaling pathway, all of which are the upstream regulators of eNOS activity. Activation of the phosphoinositide 3-kinase-Akt pathway and Hsp90 contributes to KLF2-induced increase of eNOS activity. The present results suggest that approaches inducing KLF2 activation, such as physical exercise, are effective to restore eNOS activity against diabetic endothelial dysfunction. ARTICLE HIGHLIGHTS Exercise and statins restore the endothelial expression of Krüppel-like factor 2 (KLF2), which is diminished in diabetic db/db mice. Endothelium-specific overexpression of KLF2 improves endothelium-dependent relaxation and flow-mediated dilation through increasing nitric oxide bioavailability. KLF2 promotes endothelial nitric oxide synthase (eNOS) coupling and phosphorylation in addition to its known role in eNOS transcription. KLF2 upregulates the expression of several panels of genes that regulate eNOS activity.
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Affiliation(s)
- Jiang-Yun Luo
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- School of Biomedical Sciences and Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Chak Kwong Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Lingshan Gou
- Center for Genetic Medicine, Xuzhou Maternity and Health Care Hospital, Jiangsu, China
| | - Lei He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Lei Zhao
- School of Biomedical Sciences and Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Yang Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangdong, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Chi Wai Lau
- School of Biomedical Sciences and Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Alex F Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong Special Administrative Region, China
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Cincotta AH. Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects. Int J Mol Sci 2023; 24:13255. [PMID: 37686060 PMCID: PMC10487918 DOI: 10.3390/ijms241713255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/19/2023] [Accepted: 07/27/2023] [Indexed: 09/10/2023] Open
Abstract
Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.
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Wang D, Li J, Luo G, Zhou J, Wang N, Wang S, Zhao R, Cao X, Ma Y, Liu G, Hao L. Nox4 as a novel therapeutic target for diabetic vascular complications. Redox Biol 2023; 64:102781. [PMID: 37321060 PMCID: PMC10363438 DOI: 10.1016/j.redox.2023.102781] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/03/2023] [Accepted: 06/08/2023] [Indexed: 06/17/2023] Open
Abstract
Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.
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Affiliation(s)
- Dongxia Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China; Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Jiaying Li
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Luo
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Juan Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Ning Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Shanshan Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Rui Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Xin Cao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China
| | - Yuxia Ma
- Department of Nutrition and Food Hygiene, School of Public Health, Hebei Medical University, Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, 050017, China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, Hebei International Joint Research Center for Structural Heart Disease, Hebei Key Laboratory of Cardiac Injury Repair Mechanism Study, Shijiazhuang, 050000, China.
| | - Liping Hao
- Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment, Wuhan, 430030, China.
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18
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Deng H, Li B, Shen Q, Zhang C, Kuang L, Chen R, Wang S, Ma Z, Li G. Mechanisms of diabetic foot ulceration: A review. J Diabetes 2023; 15:299-312. [PMID: 36891783 PMCID: PMC10101842 DOI: 10.1111/1753-0407.13372] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/23/2023] [Accepted: 02/16/2023] [Indexed: 03/10/2023] Open
Abstract
Diabetic foot ulcers (DFUs) are associated with complex pathogenic factors and are considered a serious complication of diabetes. The potential mechanisms underlying DFUs have been increasingly investigated. Previous studies have focused on the three aspects of diabetic peripheral vascular disease, neuropathy, and wound infections. With advances in technology, researchers have been gradually conducting studies using immune cells, endothelial cells, keratinocytes, and fibroblasts, as they are involved in wound healing. It has been reported that the upregulation or downregulation of molecular signaling pathways is essential for the healing of DFUs. With a recent increase in the awareness of epigenetics, its regulatory role in wound healing has become a much sought-after trend in the treatment of DFUs. This review focuses on four aspects involved in the pathogenesis of DFUs: physiological and pathological mechanisms, cellular mechanisms, molecular signaling pathway mechanisms, and epigenetics. Given the challenge in the treatment of DFUs, we are hopeful that our review will provide new ideas for peers.
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Affiliation(s)
- Haibo Deng
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Binghui Li
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Qian Shen
- School of Foreign StudiesZhongnan University of Economics and LawWuhanHubeiChina
| | - Chenchen Zhang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Liwen Kuang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Ran Chen
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - SiYuan Wang
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - ZhiQiang Ma
- Department of Wound Repair, Liyuan Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
| | - Gongchi Li
- Department of Hand Surgery, Union Hospital affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiChina
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Janaszak-Jasiecka A, Płoska A, Wierońska JM, Dobrucki LW, Kalinowski L. Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets. Cell Mol Biol Lett 2023; 28:21. [PMID: 36890458 PMCID: PMC9996905 DOI: 10.1186/s11658-023-00423-2] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 01/19/2023] [Indexed: 03/10/2023] Open
Abstract
Nitric oxide (NO) is one of the most important molecules released by endothelial cells, and its antiatherogenic properties support cardiovascular homeostasis. Diminished NO bioavailability is a common hallmark of endothelial dysfunction underlying the pathogenesis of the cardiovascular disease. Vascular NO is synthesized by endothelial nitric oxide synthase (eNOS) from the substrate L-arginine (L-Arg), with tetrahydrobiopterin (BH4) as an essential cofactor. Cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, aging, or smoking increase vascular oxidative stress that strongly affects eNOS activity and leads to eNOS uncoupling. Uncoupled eNOS produces superoxide anion (O2-) instead of NO, thus becoming a source of harmful free radicals exacerbating the oxidative stress further. eNOS uncoupling is thought to be one of the major underlying causes of endothelial dysfunction observed in the pathogenesis of vascular diseases. Here, we discuss the main mechanisms of eNOS uncoupling, including oxidative depletion of the critical eNOS cofactor BH4, deficiency of eNOS substrate L-Arg, or accumulation of its analog asymmetrical dimethylarginine (ADMA), and eNOS S-glutathionylation. Moreover, potential therapeutic approaches that prevent eNOS uncoupling by improving cofactor availability, restoration of L-Arg/ADMA ratio, or modulation of eNOS S-glutathionylation are briefly outlined.
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Affiliation(s)
- Anna Janaszak-Jasiecka
- Department of Medical Laboratory Diagnostics - Fahrenheit Biobank BBMRI.Pl, Medical University of Gdansk, 7 Debinki Street, 80-211, Gdansk, Poland
| | - Agata Płoska
- Department of Medical Laboratory Diagnostics - Fahrenheit Biobank BBMRI.Pl, Medical University of Gdansk, 7 Debinki Street, 80-211, Gdansk, Poland
| | - Joanna M Wierońska
- Department of Neurobiology, Polish Academy of Sciences, Maj Institute of Pharmacology, 12 Smętna Street, 31-343, Kraków, Poland
| | - Lawrence W Dobrucki
- Department of Medical Laboratory Diagnostics - Fahrenheit Biobank BBMRI.Pl, Medical University of Gdansk, 7 Debinki Street, 80-211, Gdansk, Poland.,Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.,Beckman Institute for Advanced Science and Technology, 405 N Mathews Ave, MC-251, Urbana, IL, 61801, USA.,Department of Biomedical and Translational Sciences, Carle-Illinois College of Medicine, Urbana, IL, USA
| | - Leszek Kalinowski
- Department of Medical Laboratory Diagnostics - Fahrenheit Biobank BBMRI.Pl, Medical University of Gdansk, 7 Debinki Street, 80-211, Gdansk, Poland. .,BioTechMed Centre, Department of Mechanics of Materials and Structures, Gdansk University of Technology, 11/12 Gabriela Narutowicza Street, 80-233, Gdansk, Poland.
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20
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Nitric oxide promotes cell-matrix adhesion of endothelial progenitor cells under hypoxia condition via ITGA5 CpG promoter demethylation. Biochem Biophys Res Commun 2023; 644:162-170. [PMID: 36669384 DOI: 10.1016/j.bbrc.2023.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Hypoxia or low oxygen tension causes changes in the structure and functional phenotype of the endothelial progenitor cells (EPCs). EPCs are found to be involved in angiogenesis and vascular repair. However, EPC's role in cell-matrix adhesion under hypoxia conditions is not clearly established. Nitric oxide (NO) exerts a wide range of biological functions, especially in regulating the mobilization and vascular repair of EPCs. In contrast, the link between NO and its role in cell-matrix deadhesion under hypoxia is not studied yet. Here, we investigated the protective role of NO in hypoxia-induced cell-matrix deadhesion of EPCs through an epigenetic mechanism. The EPCs were exposed to 2% hypoxia in the presence or absence of 10 μM Spermine NONOate (NO donor). The result demonstrates that hypoxia exposure intensified mitochondrial oxidative damage and energy defects. Using miScript miRNA qPCR array-based screening, the study found miR-148 as a novel target of hypoxia-induced DNMT1 activation. Mechanistically, the study discovered that hypoxia suppressed miR-148 levels and stimulated EPCs cell-matrix deadhesion via increasing DNMT1 mediated Integrin alpha-5 (ITGA5) CpG promoter hypermethylation. Treatment with a mitochondria-targeted antioxidant, MitoTEMPO, or epigenetic DNMT inhibitor, 5'-azacitidine, or miR-148 overexpression in hypoxic EPCs culture, prevented the cell-matrix deadhesion compared to hypoxic EPCs. Further, treatment of spNO or transient expression of eNOS-GFP attenuated hypoxia-induced cell-matrix deadhesion via inhibition of ITGA5 CpG island promoter methylation. In conclusion, the study provides evidence that NO is essential for cell-matrix adhesion of EPCs by epigenetically mitigating ITGA5 CpG promoter hypermethylation under hypoxia conditions. This finding uncovers the previously undefined mechanism of NO-mediated diminution of hypoxia-induced cell-matrix deadhesion and dysfunction induced by low oxygen tension.
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21
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Margolis DJ, Mitra N, Hoffstad O, Malay DS, Mirza ZK, Lantis JC, Lev-Tov HA, Kirsner RS, Ruhela D, Bhopale VM, Thom SR. Circulating endothelial precursor cells are associated with a healed diabetic foot ulcer evaluated in a prospective cohort study. Wound Repair Regen 2023; 31:128-134. [PMID: 36177665 PMCID: PMC10319405 DOI: 10.1111/wrr.13055] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 09/24/2022] [Indexed: 02/01/2023]
Abstract
The goal of this multicentre study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects, and 40.0% (28.4, 41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+ CD45dim , the univariate odds ratio was 1.19 (95% confidence interval: 0.88, 1.61) and after adjustment for wound area and wound duration, the odds ratio was (1.67 (1.16, 2.42) p = 0.006). A prognostic model using CD34+ CD45dim , wound area, and wound duration had an area under the curve of 0.75 (0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multicentred prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care.
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Affiliation(s)
- David J. Margolis
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nandita Mitra
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Ole Hoffstad
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - D. Scot Malay
- Department of Surgery, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania
| | | | - John C. Lantis
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York City, New York
| | - Hadar A. Lev-Tov
- Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida
| | - Robert S. Kirsner
- Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida
| | - Deepa Ruhela
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Veena M. Bhopale
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Stephan R. Thom
- Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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22
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Jiang M, Jiang X, Li H, Zhang C, Zhang Z, Wu C, Zhang J, Hu J, Zhang J. The role of mesenchymal stem cell-derived EVs in diabetic wound healing. Front Immunol 2023; 14:1136098. [PMID: 36926346 PMCID: PMC10011107 DOI: 10.3389/fimmu.2023.1136098] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/09/2023] [Indexed: 03/04/2023] Open
Abstract
Diabetic foot is one of the most common complications of diabetes, requiring repeated surgical interventions and leading to amputation. In the absence of effective drugs, new treatments need to be explored. Previous studies have found that stem cell transplantation can promote the healing of chronic diabetic wounds. However, safety issues have limited the clinical application of this technique. Recently, the performance of mesenchymal stem cells after transplantation has been increasingly attributed to their production of exocrine functional derivatives such as extracellular vesicles (EVs), cytokines, and cell-conditioned media. EVs contain a variety of cellular molecules, including RNA, DNA and proteins, which facilitate the exchange of information between cells. EVs have several advantages over parental stem cells, including a high safety profile, no immune response, fewer ethical concerns, and a reduced likelihood of embolism formation and carcinogenesis. In this paper, we summarize the current knowledge of mesenchymal stem cell-derived EVs in accelerating diabetic wound healing, as well as their potential clinic applications.
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Affiliation(s)
- Min Jiang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Xupin Jiang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Hongmei Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Can Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Ze Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Chao Wu
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Junhui Zhang
- Department of Geriatic Oncology, Department of Palliative Care, Department of Clinical Nutrition, Chongqing University Cancer Hospital, Chongqing, China.,Endocrinology Department, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiongyu Hu
- Endocrinology Department, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
| | - Jiaping Zhang
- Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, China
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23
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Peng C, Yang LJ, Zhang C, Jiang Y, Shang LWX, He JB, Zhou ZW, Tao X, Tie L, Chen AF, Xie HH. Low-dose nifedipine rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice. Acta Pharmacol Sin 2023; 44:44-57. [PMID: 35882957 PMCID: PMC9813355 DOI: 10.1038/s41401-022-00948-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 06/24/2022] [Indexed: 01/18/2023]
Abstract
It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cell (EPC) dysfunction is a key contributor to diabetic vascular complications. In the present study we evaluated whether low-dose nifedipine could rescue impaired EPC-mediated angiogenesis and prevent cardiovascular complications in diabetic mice. Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg-1·d-1, i.p.). Diabetic mice were treated with low-dose nifedipine (1.5 mg·kg-1·d-1, i.g.) for six weeks. Then, circulating EPCs in the peripheral blood were quantified, and bone marrow-derived EPCs (BM-EPCs) were prepared. We showed that administration of low-dose nifedipine significantly increased circulating EPCs, improved BM-EPCs function, promoted angiogenesis, and reduced the cerebral ischemic injury in diabetic mice. Furthermore, we found that low-dose nifedipine significantly increased endothelial nitric oxide synthase (eNOS) expression and intracellular NO levels, and decreased the levels of intracellular O2.- and thrombospondin-1/2 (TSP-1/2, a potent angiogenesis inhibitor) in BM-EPCs of diabetic mice. In cultured BM-EPCs, co-treatment with nifedipine (0.1, 1 μM) dose-dependently protected against high-glucose-induced impairment of migration, and suppressed high-glucose-induced TSP-1 secretion and superoxide overproduction. In mice with middle cerebral artery occlusion, intravenous injection of diabetic BM-EPCs treated with nifedipine displayed a greater ability to promote local angiogenesis and reduce cerebral ischemic injury compared to injection of diabetic BM-EPCs treated with vehicle, and the donor-derived BM-EPCs homed to the recipient ischemic brain. In conclusion, low-dose nifedipine can enhance EPCs' angiogenic potential and protect against cerebral ischemic injury in diabetic mice. It is implied that chronic treatment with low-dose nifedipine may be a safe and economic manner to prevent ischemic diseases (including stroke) in diabetes.
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Affiliation(s)
- Cheng Peng
- School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Li-Jun Yang
- School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chuan Zhang
- School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Yu Jiang
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Liu-Wen-Xin Shang
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Jia-Bei He
- School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhen-Wei Zhou
- School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xia Tao
- Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China
| | - Lu Tie
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China.
| | - Alex F Chen
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - He-Hui Xie
- School of Public Health and Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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24
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Lee CH, Huang CH, Hung KC, Huang SC, Kuo CC, Liu SJ. Nanofibrous Vildagliptin/PLGA Membranes Accelerate Diabetic Wound Healing by Angiogenesis. Pharmaceuticals (Basel) 2022; 15:1358. [PMID: 36355530 PMCID: PMC9696371 DOI: 10.3390/ph15111358] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
The inhibition of dipeptidyl peptidase-4 (DPP4) significantly enhances the wound closure rate in diabetic patients with chronic foot ulcers. DPP4 inhibitors are only prescribed for enteral, but topical administration, if feasible, to a wound would have more encouraging outcomes. Nanofibrous drug-eluting poly-D-L-lactide-glycolide (PLGA) membranes that sustainably release a high concentration of vildagliptin were prepared to accelerate wound healing in diabetes. Solutions of vildagliptin and PLGA in hexafluoroisopropanol were electrospun into nanofibrous biodegradable membranes. The concentration of the drug released in vitro from the vildagliptin-eluting PLGA membranes was evaluated, and it was found that effective bioactivity of vildagliptin can be discharged from the nanofibrous vildagliptin-eluting membranes for 30 days. Additionally, the electrospun nanofibrous PLGA membranes modified by blending with vildagliptin had smaller fiber diameters (336.0 ± 69.1 nm vs. 743.6 ± 334.3 nm, p < 0.001) and pore areas (3405 ± 1437 nm2 vs. 8826 ± 4906 nm2, p < 0.001), as well as a higher hydrophilicity value (95.2 ± 2.2° vs. 113.9 ± 4.9°, p = 0.004), and showed a better water-retention ability within 24 h compared with PLGA membranes. The vildagliptin-eluting PLGA membrane also enhanced the diabetic wound closure rate for two weeks (11.4 ± 3.0 vs. 18.7 ± 2.6 %, p < 0.001) and the level of the angiogenesis using CD31 expression (1.73 ± 0.39 vs. 0.45 ± 0.17 p = 0.006 for Western blot; 2.2 ± 0.5 vs. 0.7 ± 0.1, p < 0.001 for immunofluorescence). These results demonstrate that nanofibrous drug-eluting PLGA membranes loaded with vildagliptin are an effective agent for sustained drug release and, therefore, for accelerating cutaneous wound healing in the management of diabetic wounds.
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Affiliation(s)
- Chen-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Chien-Hao Huang
- Linkou Medical Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Kuo-Chun Hung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Shu-Chun Huang
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, New Taipei Municipal Tucheng Hospital, New Taipei 23652, Taiwan
- Department of Physical Medicine & Rehabilitation, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chi-Ching Kuo
- Research and Development Center of Smart Textile Technology, Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 10608, Taiwan
| | - Shih-Jung Liu
- Bone and Joint Research Center, Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan
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25
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Keller AC, Chun JH, Knaub L, Henckel M, Hull S, Scalzo R, Pott G, Walker L, Reusch J. Thermoneutrality induces vascular dysfunction and impaired metabolic function in male Wistar rats: a new model of vascular disease. J Hypertens 2022; 40:2133-2146. [PMID: 35881464 PMCID: PMC9553250 DOI: 10.1097/hjh.0000000000003153] [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: 10/26/2021] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Cardiovascular disease is of paramount importance, yet there are few relevant rat models to investigate its pathology and explore potential therapeutics. Housing at thermoneutral temperature (30 °C) is being employed to humanize metabolic derangements in rodents. We hypothesized that housing rats in thermoneutral conditions would potentiate a high-fat diet, resulting in diabetes and dysmetabolism, and deleteriously impact vascular function, in comparison to traditional room temperature housing (22 °C). METHODS Male Wistar rats were housed at either room temperature or thermoneutral temperatures for 16 weeks on either a low or high-fat diet. Glucose and insulin tolerance tests were conducted at the beginning and end of the study. At the study's conclusion, vasoreactivity and mitochondrial respiration of aorta and carotid were conducted. RESULTS We observed diminished vasodilation in vessels from thermoneutral rats ( P < 0.05), whereas high-fat diet had no effect. This effect was also observed in endothelium-denuded aorta in thermoneutral rats ( P < 0.05). Vasoconstriction was significantly elevated in aorta of thermoneutral rats ( P < 0.05). Diminished nitric oxide synthase activity and nitrotyrosine, and elevated glutathione activity were observed in aorta from rats housed under thermoneutral conditions, indicating a climate of lower nitric oxide and excess reactive oxygen species in aorta. Thermoneutral rat aorta also demonstrated less mitochondrial respiration with lipid substrates compared with the controls ( P < 0.05). CONCLUSION Our data support that thermoneutrality causes dysfunctional vasoreactivity, decreased lipid mitochondrial metabolism, and modified cellular signaling. These are critical observations as thermoneutrality is becoming prevalent for translational research models. This new model of vascular dysfunction may be useful for dissection of targetable aspects of cardiovascular disease and is a novel and necessary model of disease.
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Affiliation(s)
- Amy C. Keller
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | | | - L.A. Knaub
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | - M.M. Henckel
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | - S.E. Hull
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | - R.L. Scalzo
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | - G.B. Pott
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
| | - L.A. Walker
- Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - J.E.B. Reusch
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado Anschutz Medical Campus
- Rocky Mountain Regional VA Medical Center, Aurora, Colorado
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26
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Zaidi SK, Hoda MN, Tabrez S, Khan MI. Pharmacological Inhibition of Class III Alcohol Dehydrogenase 5: Turning Remote Ischemic Conditioning Effective in a Diabetic Stroke Model. Antioxidants (Basel) 2022; 11:antiox11102051. [PMID: 36290774 PMCID: PMC9598110 DOI: 10.3390/antiox11102051] [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: 07/26/2022] [Revised: 10/02/2022] [Accepted: 10/10/2022] [Indexed: 11/24/2022] Open
Abstract
The restoration of cerebral blood flow (CBF) to achieve brain tissue oxygenation (PbtO2) is the primary treatment for ischemic stroke, a significant cause of adult mortality and disability worldwide. Nitric oxide (NO) and its bioactive s-nitrosylated (SNO) reservoirs, such as s-nitrosoglutathione (GSNO), induce hypoxic vasodilation to enhance CBF during ischemia. The endogenous pool of SNOs/GSNO is enhanced via the activation of endothelial NO synthase (eNOS/NOS3) and by the suppression of class III alcohol dehydrogenase 5 (ADH5), also known as GSNO reductase (GSNOR). Remote ischemic conditioning (RIC), which augments NOS3 activity and SNO, is an emerging therapy in acute stroke. However, RIC has so far shown neutral effects in stroke clinical trials. As the majority of stroke patients are presented with endothelial dysfunctions and comorbidities, we tested the hypothesis that NOS3 dysfunction and diabetes will abolish the protective effects of RIC therapy in stroke, and the prior inhibition of GSNOR will turn RIC protective. Our data demonstrate that RIC during thrombotic stroke failed to enhance the CBF and the benefits of thrombolysis in NOS3 mutant (NOS3+/−) mice, a genetic model of NOS3 dysfunction. Interestingly, thrombotic stroke in diabetic mice enhanced the activity of GSNOR as early as 3 h post-stroke without decreasing the plasma nitrite (NO2−). In thrombotic stroke, neither a pharmacological inhibitor of GSNOR (GRI) nor RIC therapy alone was protective in diabetic mice. However, prior treatment with GRI followed by RIC enhanced the CBF and improved recovery. In a reperfused stroke model, the GRI–RIC combination therapy in diabetic mice augmented PbtO2, a translatory signature of successful microvascular reflow. In addition, RIC therapy unexpectedly increased the inflammatory markers at 6 h post-stroke in diabetic stroke that were downregulated in combination with GRI while improving the outcomes. Thus, we conclude that preexisting NOS3 dysfunctions due to comorbidities may neutralize the benefits of RIC in stroke, which can be turned protective in combination with GRI. Our findings may support the future clinical trial of RIC in comorbid stroke. Further studies are warranted to test and develop SNO reservoirs as the blood-associated biomarker to monitor the response and efficacy of RIC therapy in stroke.
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Affiliation(s)
- Syed Kashif Zaidi
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence:
| | - Md Nasrul Hoda
- Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA
| | - Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
- Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammad Imran Khan
- Department of Biochemistry, Faculty of Life Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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27
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Mader MMD, Czorlich P. The role of L-arginine metabolism in neurocritical care patients. Neural Regen Res 2022; 17:1446-1453. [PMID: 34916417 PMCID: PMC8771107 DOI: 10.4103/1673-5374.327331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/21/2021] [Accepted: 07/25/2021] [Indexed: 11/20/2022] Open
Abstract
Nitric oxide is an important mediator of vascular autoregulation and is involved in pathophysiological changes after acute neurological disorders. Nitric oxide is generated by nitric oxide synthases from the amino acid L-arginine. L-arginine can also serve as a substrate for arginases or lead to the generation of dimethylarginines, asymmetric dimethylarginine, and symmetric dimethylarginine, by methylation. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase and can lead to endothelial dysfunction. This review discusses the role of L-arginine metabolism in patients suffering from acute and critical neurological disorders often requiring neuro-intensive care treatment. Conditions addressed in this review include intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and traumatic brain injury. Recent therapeutic advances in the field are described including current randomized controlled trials for traumatic brain injuries and hemorrhagic stroke.
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Affiliation(s)
- Marius Marc-Daniel Mader
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Patrick Czorlich
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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28
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A Randomized Controlled Trial Evaluating Outcome Impact of Cilostazol in Patients with Coronary Artery Disease or at a High Risk of Cardiovascular Disease. J Pers Med 2022; 12:jpm12060938. [PMID: 35743723 PMCID: PMC9225272 DOI: 10.3390/jpm12060938] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 12/25/2022] Open
Abstract
Previous studies found that cilostazol has a favorable effect on glucose and lipid homeostasis, endothelial function, atherosclerosis, and vasculo-angiogenesis. However, it is poorly understood whether these effects can translate into better clinical outcomes. This study investigated the outcome effect of cilostazol in patients with coronary artery disease (CAD) or at a high risk of cardiovascular (CV) disease. We conducted a randomized, double-blind, placebo-controlled trial involving 266 patients who received cilostazol, 200 mg/day (n = 134) or placebo (n = 132). Pre-specified clinical endpoints including composite major adverse cardiovascular events (MACE) (CV death, non-fatal myocardial infarct, non-fatal stroke, hospitalization for heart failure, or unplanned coronary revascularization), the composite major coronary event (MCE) and major adverse CV and cerebrovascular event (MACCE), were prospectively assessed. The mean duration of follow-up was 2.9 years. Relative to placebo, cilostazol treatment had a borderline effect on risk reduction of MACE (hazard ratio [HR], 0.67; 95% confidence interval (CI), 0.34–1.33), whereas the beneficial effect in favor of cilostazol was significant in patients with diabetes mellitus or a history of percutaneous coronary intervention (p for interaction, 0.02 and 0.06, respectively). Use of cilostazol, significantly reduced the risk of MCE (HR, 0.38; 95% CI, 0.17–0.86) and MACCE (HR, 0.47; 95% CI, 0.23–0.96). A significantly lower risk of angina pectoris (HR, 0.38; 95% CI, 0.17–0.86) was also observed in the cilostazol group. After multi-variable adjustment, cilostazol treatment independently predicted a lower risk of MCE. In conclusion, these results suggest cilostazol may have beneficial effects in patients with CAD or at a high risk of CV disease.
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Shishikura D, Octavia Y, Hayat U, Thondapu V, Barlis P. Atherogenesis and Inflammation. Interv Cardiol 2022. [DOI: 10.1002/9781119697367.ch1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Zhao L, Zhang CL, He L, Chen Q, Liu L, Kang L, Liu J, Luo JY, Gou L, Qu D, Song W, Lau CW, Ko H, Mok VCT, Tian XY, Wang L, Huang Y. Restoration of Autophagic Flux Improves Endothelial Function in Diabetes Through Lowering Mitochondrial ROS-Mediated eNOS Monomerization. Diabetes 2022; 71:1099-1114. [PMID: 35179568 DOI: 10.2337/db21-0660] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 02/10/2022] [Indexed: 11/13/2022]
Abstract
Endothelial nitric oxide synthase (eNOS) monomerization and uncoupling play crucial roles in mediating vascular dysfunction in diabetes, although the underlying mechanisms are still incompletely understood. Increasing evidence indicates that autophagic dysregulation is involved in the pathogenesis of diabetic endothelial dysfunction; however, whether autophagy regulates eNOS activity through controlling eNOS monomerization or dimerization remains elusive. In this study, autophagic flux was impaired in the endothelium of diabetic db/db mice and in human endothelial cells exposed to advanced glycation end products or oxidized low-density lipoprotein. Inhibition of autophagic flux by chloroquine or bafilomycin A1 were sufficient to induce eNOS monomerization and lower nitric oxide bioavailability by increasing mitochondrial reactive oxygen species (mtROS). Restoration of autophagic flux by overexpressing transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, decreased endothelial cell oxidative stress, increased eNOS dimerization, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Inhibition of mammalian target of rapamycin kinase (mTOR) increased TFEB nuclear localization, reduced mtROS accumulation, facilitated eNOS dimerization, and enhanced EDR in db/db mice. Moreover, calorie restriction also increased TFEB expression, improved autophagic flux, and restored EDR in the aortas of db/db mice. Taken together, the findings of this study reveal that mtROS-induced eNOS monomerization is closely associated with the impaired TFEB-autophagic flux axis leading to endothelial dysfunction in diabetic mice.
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Affiliation(s)
- Lei Zhao
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Cheng-Lin Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Lei He
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Qinghua Chen
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Limei Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lijing Kang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Jian Liu
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jiang-Yun Luo
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Lingshan Gou
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Dan Qu
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wencong Song
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Wai Lau
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Ho Ko
- Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent C T Mok
- Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Yu Tian
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Li Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Yu Huang
- Shenzhen Research Institute and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
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Sen A, Thakkar H, Vincent V, Rai S, Singh A, Mohanty S, Roy A, Ramakrishnan L. Endothelial colony forming cells' tetrahydrobiopterin level in coronary artery disease patients and its association with circulating endothelial progenitor cells. Can J Physiol Pharmacol 2022; 100:473-485. [PMID: 35180005 DOI: 10.1139/cjpp-2021-0548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelial colony forming cells (ECFCs) participate in neovascularization. Endothelial nitric oxide synthase (eNOS) derived NO· helps in homing of endothelial progenitor cells (EPCs) at the site of vascular injury. The enzyme cofactor tetrahydrobiopterin (BH4) stabilizes the catalytic active state of eNOS. Association of intracellular ECFCs biopterins and ratio of reduced to oxidized biopterin (BH4:BH2) with circulatory EPCs and ECFCs functionality have not been studied. We investigated ECFCs biopterin levels and its association with circulatory EPCs as well as ECFCs proliferative potential in terms of day of appearance in culture. Circulatory EPCs were enumerated by flowcytometry in 53 coronary artery disease (CAD) patients and 42 controls. ECFCs were cultured, characterized, and biopterin levels assessed by high performance liquid chromatography. Appearance of ECFCs' colony and their number were recorded. Circulatory EPCs were significantly lower in CAD and ECFCs appeared in 56% and 33% of CAD and control subjects, respectively. Intracellular BH4 and BH4:BH2 were significantly reduced in CAD. BH4:BH2 was positively correlated with circulatory EPCs (p = 0.01), and negatively with day of appearance of ECFCs (p = 0.04). Circulatory EPCs negatively correlated with ECFCs appearance (p = 0.02). These findings suggest the role of biopterins in maintaining circulatory EPCs and functional integrity of ECFCs.
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Affiliation(s)
- Atanu Sen
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Himani Thakkar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Vinnyfred Vincent
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Rai
- Department of Laboratory Oncology, Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Archna Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility, DBT-Center of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi, India
| | - Ambuj Roy
- Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
| | - Lakshmy Ramakrishnan
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Peracaula M, Torres D, Poyatos P, Luque N, Rojas E, Obrador A, Orriols R, Tura-Ceide O. Endothelial Dysfunction and Cardiovascular Risk in Obstructive Sleep Apnea: A Review Article. Life (Basel) 2022; 12:537. [PMID: 35455027 PMCID: PMC9025914 DOI: 10.3390/life12040537] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/23/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Obstructive sleep apnea (OSA) is a respiratory condition during sleep caused by repeated pauses in breathing due to upper airway obstruction. It is estimated that OSA affects 30% of the population, but only 10% are well diagnosed due to the absence of a well-defined symptomatology and poor screening tools for early diagnosis. OSA is associated to an endothelial dysfunction inducing several biological responses such as hypoxia, hypercapnia and oxidative stress, among others. OSA also triggers respiratory, nervous, metabolic, humoral and immunity system activations that increase the possibility of suffering a cardiovascular (CV) disease. In this review, we expose different studies that show the relationship between OSA and endothelial dysfunction and its association with CV pathologies like hypertension, and we define the most well-known treatments and their limitations. Additionally, we describe the potential future directions in OSA research, and we report clinical features such as endothelial progenitor cell alterations that could act as biomarkers for the development of new diagnostic tools and target therapies.
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Affiliation(s)
- Miriam Peracaula
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Daniela Torres
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Paula Poyatos
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Neus Luque
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Eric Rojas
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Anton Obrador
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Ramon Orriols
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital of Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; (M.P.); (D.T.); (P.P.); (N.L.); (E.R.); (A.O.)
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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Sen A, Singh A, Roy A, Mohanty S, Naik N, Kalaivani M, Ramakrishnan L. Role of endothelial colony forming cells (ECFCs) Tetrahydrobiopterin (BH4) in determining ECFCs functionality in coronary artery disease (CAD) patients. Sci Rep 2022; 12:3076. [PMID: 35197509 PMCID: PMC8866483 DOI: 10.1038/s41598-022-06758-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 01/31/2022] [Indexed: 01/05/2023] Open
Abstract
Nitric oxide (NO.) is critical for functionality of endothelial colony forming cells (ECFCs). Dimerization of endothelial nitric oxide synthase (eNOS) is must to produce NO. and tetrahydrobiopterin (BH4) plays a crucial role in stabilizing this state. We investigated BH4 level in ECFCs and its effect on ECFCs functionality in CAD patients. Intracellular biopterin levels and ECFCs functionality in terms of cell viability, adhesion, proliferation, in vitro wound healing and angiogenesis were assessed. Guanosine Triphosphate Cyclohydrolase-1 (GTPCH-1) expression was studied in ECFCs. Serum total reactive oxygen/nitrogen species was measured and effect of nitrosative stress on ECFC's biopterins level and functionality were evaluated by treating with 3-morpholino sydnonimine (SIN-1). BH4 level was significantly lower in ECFCs from CAD patients. Cell proliferation, wound closure reflecting cellular migration as well as in vitro angiogenesis were impaired in ECFCs from CAD patients. Wound healing capacity and angiogenesis were positively correlated with ECFC's BH4. A negative effect of nitrosative stress on biopterins level and cell functionality was observed in SIN-1 treated ECFCs. ECFCs from CAD exhibited impaired functionality and lower BH4 level. Association of BH4 with wound healing capacity and angiogenesis suggest its role in maintaining ECFC's functionality. Oxidative stress may be a determinant of intracellular biopterin levels.
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Affiliation(s)
- Atanu Sen
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Archna Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Ambuj Roy
- Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi, India
| | - Nitish Naik
- Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
| | - Mani Kalaivani
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Lakshmy Ramakrishnan
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
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Zhu QQ, Li DL, Wang X, Wang YS, Zeng QL, Qiu CY, He YY, Wu ZH, He YJ, Shang T, Zhang HK. The role of RAGE, MAPK and NF-κB pathway in the advanced glycation end-products induced HUVECs dysfunction. VASCULAR INVESTIGATION AND THERAPY 2022. [DOI: 10.4103/2589-9686.360874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Sen A, Vincent V, Thakkar H, Abraham R, Ramakrishnan L. Beneficial Role of Vitamin D on Endothelial Progenitor Cells (EPCs) in Cardiovascular Diseases. J Lipid Atheroscler 2022; 11:229-249. [PMID: 36212746 PMCID: PMC9515729 DOI: 10.12997/jla.2022.11.3.229] [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: 02/04/2022] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 11/23/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death in the world. Endothelial progenitor cells (EPCs) are currently being explored in the context of CVD risk. EPCs are bone marrow derived progenitor cells involved in postnatal endothelial repair and neovascularization. A large body of evidence from clinical, animal, and in vitro studies have shown that EPC numbers in circulation and their functionality reflect endogenous vascular regenerative capacity. Traditionally vitamin D is known to be beneficial for bone health and calcium metabolism and in the last two decades, its role in influencing CVD and cancer risk has generated significant interest. Observational studies have shown that low vitamin D levels are associated with an adverse cardiovascular risk profile. Still, Mendelian randomization studies and randomized control trials (RCTs) have not shown significant effects of vitamin D on cardiovascular events. The criticism regarding the RCTs on vitamin D and CVD is that they were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals. Overall, the association between vitamin D and CVD remains inconclusive. Recent clinical and experimental studies have demonstrated the beneficial role of vitamin D in increasing the circulatory level of EPC as well as their functionality. In this review we present evidence supporting the beneficial role of vitamin D in CVD through its modulation of EPC homeostasis.
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Affiliation(s)
- Atanu Sen
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Vinnyfred Vincent
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Himani Thakkar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Ransi Abraham
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Lakshmy Ramakrishnan
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Choudhery MS. Strategies to improve regenerative potential of mesenchymal stem cells. World J Stem Cells 2021; 13:1845-1862. [PMID: 35069986 PMCID: PMC8727227 DOI: 10.4252/wjsc.v13.i12.1845] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/31/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
In the last few decades, stem cell-based therapies have gained attention worldwide for various diseases and disorders. Adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials. Although MSCs have high self-renewal as well as differentiation potential, such abilities are compromised with "advanced age" and "disease status" of the donor. Similarly, cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells. It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies, however; autologous use of stem cells for such patients (aged and diseased) does not seem to give optimal results due to their compromised potential. In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs. It is therefore essential to improve the regenerative potential of stem cells compromised due to "in vitro expansion", "donor age" and "donor disease status" for their successful autologous use. The current review has been organized to address the age and disease depleted function of resident adult stem cells, and the strategies to improve their potential. To combat the problem of decline in the regenerative potential of cells, this review focuses on the strategies that manipulate the cell environment such as hypoxia, heat shock, caloric restriction and preconditioning with different factors.
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Affiliation(s)
- Mahmood S Choudhery
- Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Punjab, Pakistan
- Department of Genetics and Molecular Biology, University of Health Sciences, Lahore 54600, Punjab, Pakistan.
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Zhang Y, Mao XD, Cao AL, Chu S, Li ZJ, Wang YM, Peng W, Wang L, Wang H. Astragaloside IV prevents endothelial dysfunction by improving oxidative stress in streptozotocin-induced diabetic mouse aortas. Exp Ther Med 2021; 22:1197. [PMID: 34584542 PMCID: PMC8422382 DOI: 10.3892/etm.2021.10631] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/15/2021] [Indexed: 12/17/2022] Open
Abstract
Oxidative stress serves a role in endothelial dysfunction exhibited by patients with diabetes mellitus. Astragaloside IV (AS-IV) is a major active ingredient of Radix Astragali, which is considered to exhibit vasoprotective effects through unknown mechanisms. Thus, the current study was performed to investigate the protective effects of AS-IV in streptozotocin (STZ)-induced endothelial dysfunction and to explore whether antioxidant mechanisms were involved. The protective effects of AS-IV on the endothelium-dependent relaxation and contraction of aortic rings were determined by isometric tension recordings. NADPH subunits and endothelial nitric oxide synthase (eNOS) expression was identified via western blotting. Superoxide dismutase and malondialdehyde levels were assayed using ELISA. Furthermore, the generation of reactive oxygen species (ROS) and nitric oxide (NO) was detected via dihydroethidium and 4,5-diaminofluorescein diacetate staining, respectively. The results revealed that STZ-injected mice exhibited increased aortic endothelium-dependent vasoconstriction and decreased vasorelaxation to acetylcholine. However, AS-IV treatment reversed these effects. NG-nitro-L-arginine was subsequently used to completely inhibit impaired relaxation. Accordingly, impaired NO generation was restored following AS-IV treatment by increasing eNOS phosphorylation levels. Furthermore, ROS formation was also depressed following AS-IV treatment compared with that in STZ-injected mice. AS-IV also decreased the expression of various NADPH subunits, including human neutrophil cytochrome b light chain, neutrophil cytosolic factor 1, NADPH oxidase (NOX)2, NOX4 and Rac-1. The results of the current study may provide novel evidence that diabetes-induced vascular injury arises from either the inhibition of eNOS or the activation of NOX-derived ROS generation. In addition, the results warrant further investigation into the application of AS-IV treatment, leading to the improvement of oxidative stress, in patients with diabetes exhibiting endothelial dysfunction.
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Affiliation(s)
- Yang Zhang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Xiao-Dong Mao
- Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Ai-Li Cao
- Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Shuang Chu
- Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Zhi-Jun Li
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Yun-Man Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Wen Peng
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Li Wang
- Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Hao Wang
- Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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Alaeddine LM, Harb F, Hamza M, Dia B, Mogharbil N, Azar NS, Noureldein MH, El Khoury M, Sabra R, Eid AA. Pharmacological regulation of cytochrome P450 metabolites of arachidonic acid attenuates cardiac injury in diabetic rats. Transl Res 2021; 235:85-101. [PMID: 33746109 DOI: 10.1016/j.trsl.2021.03.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/13/2021] [Accepted: 03/11/2021] [Indexed: 12/17/2022]
Abstract
Diabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-β axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM.
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Affiliation(s)
- Lynn M Alaeddine
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Frederic Harb
- Department of Biology, Faculty of Sciences, Lebanese University, Fanar, Lebanon
| | - Maysaa Hamza
- Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Batoul Dia
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Nahed Mogharbil
- Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Nadim S Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Mohamed H Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Mirella El Khoury
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Ramzi Sabra
- Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon.
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Rusin A, Li M, Cocchetto A, Seymour C, Mothersill C. Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome. Med Hypotheses 2021; 154:110647. [PMID: 34358921 DOI: 10.1016/j.mehy.2021.110647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/19/2021] [Accepted: 07/25/2021] [Indexed: 12/13/2022]
Abstract
Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure. Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS). This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism. Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS. This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress. Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations. Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.
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Affiliation(s)
- Andrej Rusin
- Department of Biology, McMaster University, Hamilton, ON Canada.
| | - Megan Li
- Department of Physics and Astronomy, McMaster University, Department of Physics and Astronomy, McMaster University, Hamilton, ON Canada
| | - Alan Cocchetto
- National CFIDS Foundation Inc., 103 Aletha Road, Needham, MA USA
| | - Colin Seymour
- Department of Biology, McMaster University, Hamilton, ON Canada
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Marino F, Scalise M, Cianflone E, Salerno L, Cappetta D, Salerno N, De Angelis A, Torella D, Urbanek K. Physical Exercise and Cardiac Repair: The Potential Role of Nitric Oxide in Boosting Stem Cell Regenerative Biology. Antioxidants (Basel) 2021; 10:1002. [PMID: 34201562 PMCID: PMC8300666 DOI: 10.3390/antiox10071002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/14/2021] [Accepted: 06/19/2021] [Indexed: 12/11/2022] Open
Abstract
Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the "nitroso-redox imbalance". Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.
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Affiliation(s)
- Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (F.M.); (M.S.); (L.S.)
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (F.M.); (M.S.); (L.S.)
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (N.S.)
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (F.M.); (M.S.); (L.S.)
| | - Donato Cappetta
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.)
| | - Nadia Salerno
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (N.S.)
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.)
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (F.M.); (M.S.); (L.S.)
| | - Konrad Urbanek
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (F.M.); (M.S.); (L.S.)
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Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches. Int J Mol Sci 2021; 22:ijms22136667. [PMID: 34206404 PMCID: PMC8267891 DOI: 10.3390/ijms22136667] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.
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Qu K, Cha H, Ru Y, Que H, Xing M. Buxuhuayu decoction accelerates angiogenesis by activating the PI3K-Akt-eNOS signalling pathway in a streptozotocin-induced diabetic ulcer rat model. JOURNAL OF ETHNOPHARMACOLOGY 2021; 273:113824. [PMID: 33581257 DOI: 10.1016/j.jep.2021.113824] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/27/2020] [Accepted: 01/10/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Buxuhuayu decoction (BXHYD) has been frequently used to treat patients with diabetic ulcers (DUs), without notable adverse reactions. However, the related molecular mechanism remains unelucidated. AIM OF THE STUDY This study assessed the potential mechanism of BXHYD against DUs by using network pharmacology and animal experiments. MATERIALS AND METHODS First, high-performance liquid chromatography (HPLC) was used for quality control of BXHYD. Further, the hub compounds and targets were screened from the Active Compound-Targets (ACT) network and the protein and protein interaction (PPI) network. Enrichment analysis was performed using DAVID, and molecular docking technology was used to identify active compounds that may play a key role in pub targets. Finally, a DUs animal model was established and used to elucidate the effect of BXHYD on the PI3K/Akt/eNOS signalling pathway. RESULTS (1) Calycosin-7-glucoside, amygdalin, and tanshinone iiA were detected in the freeze-dried powder of BXHYD. (2) Twelve hub compounds and eight hub targets were screened using the ACT and PPI networks. Through molecular docking, it was found that the four hub targets (TP53, IL6, VEGFA, and AKT1) binds luteolin and quercetin more tightly. (3) BXHYD is most likely to promote angiogenesis and wound healing by activating the PI3K/Akt/eNOS signalling pathway. CONCLUSIONS This research revealed that BXHYD might activate the PI3K/Akt/eNOS signalling pathway to promote DUs healing. These findings support the clinical use of BXHYD and provide the foundation for its subsequent studies.
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Affiliation(s)
- Keshen Qu
- Department of Traditional Chinese Surgery, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - HuiJung Cha
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Yi Ru
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Huafa Que
- Department of Traditional Chinese Surgery, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| | - Meng Xing
- Department of Dermatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, 710003, China.
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Ezrokhi M, Zhang Y, Luo S, Cincotta AH. Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet. Int J Mol Sci 2021; 22:ijms22116142. [PMID: 34200262 PMCID: PMC8201259 DOI: 10.3390/ijms22116142] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 12/31/2022] Open
Abstract
The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug's cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease. Therefore, this study investigated the impact of bromocriptine treatment upon biomarkers of vascular oxidative/nitrosative stress (including the pro-oxidative/nitrosative stress enzymes of NADPH oxidase 4, inducible nitric oxide (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), the pro-inflammatory/pro-oxidative marker GTP cyclohydrolase 1 (GTPCH 1), and the pro-vascular health enzyme, soluble guanylate cyclase (sGC) as well as the plasma level of thiobarbituric acid reactive substances (TBARS), a circulating marker of systemic oxidative stress), in hypertensive SHR rats held on a high fat diet to induce metabolic syndrome. Inasmuch as the central nervous system (CNS) dopaminergic activities both regulate and are regulated by CNS circadian pacemaker circuitry, this study also investigated the time-of-day-dependent effects of bromocriptine treatment (10 mg/kg/day at either 13 or 19 h after the onset of light (at the natural waking time or late during the activity period, respectively) among animals held on 14 h daily photoperiods for 16 days upon such vascular biomarkers of vascular redox state, several metabolic syndrome parameters, and mediobasal hypothalamic (MBH) mRNA expression levels of neuropeptides neuropeptide Y (NPY) and agouti-related protein (AgRP) which regulate the peripheral fuel metabolism and of mRNA expression of other MBH glial and neuronal cell genes that support such metabolism regulating neurons in this model system. Such bromocriptine treatment at ZT 13 improved (reduced) biomarkers of vascular oxidative/nitrosative stress including plasma TBARS level, aortic NADPH oxidase 4, iNOS and GTPCH 1 levels, and improved other markers of coupled eNOS function, including increased sGC protein level, relative to controls. However, bromocriptine treatment at ZT 19 produced no improvement in either coupled eNOS function or sGC protein level. Moreover, such ZT 13 bromocriptine treatment reduced several metabolic syndrome parameters including fasting insulin and leptin levels, as well as elevated systolic and diastolic blood pressure, insulin resistance, body fat store levels and liver fat content, however, such effects of ZT 19 bromocriptine treatment were largely absent versus control. Finally, ZT 13 bromocriptine treatment reduced MBH NPY and AgRP mRNA levels and mRNA levels of several MBH glial cell/neuronal genes that code for neuronal support/plasticity proteins (suggesting a shift in neuronal structure/function to a new metabolic control state) while ZT 19 treatment reduced only AgRP, not NPY, and was with very little effect on such MBH glial cell genes expression. These findings indicate that circadian-timed bromocriptine administration at the natural circadian peak of CNS dopaminergic activity (that is diminished in insulin resistant states), but not outside this daily time window when such CNS dopaminergic activity is naturally low, produces widespread improvements in biomarkers of vascular oxidative stress that are associated with the amelioration of metabolic syndrome and reductions in MBH neuropeptides and gene expressions known to facilitate metabolic syndrome. These results of such circadian-timed bromocriptine treatment upon vascular pathology provide potential mechanisms for the observed marked reductions in adverse cardiovascular events with circadian-timed bromocriptine-QR therapy (similarly timed to the onset of daily waking as in this study) of type 2 diabetes subjects and warrant further investigations into related mechanisms and the potential application of such intervention to prediabetes and metabolic syndrome patients as well.
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Shoeibi S, Mahdipour E, Mohammadi S, Moohebati M, Ghayour-Mobarhan M. Treatment of atherosclerosis through transplantation of endothelial progenitor cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH) in rabbits. Int J Cardiol 2021; 331:189-198. [PMID: 33535073 DOI: 10.1016/j.ijcard.2021.01.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/30/2020] [Accepted: 01/11/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Endothelial dysfunction is a key event in the development of vascular diseases, including atherosclerosis. Endothelial progenitor cells (EPCs) play an important role in vascular repair. Decreased dimethylarginine dimethylaminohydrolase (DDAH) activity is observed in several pathological conditions, and it is associated with an increased risk of vascular disease. We hypothesized that bone marrow-derived EPCs and combination therapy with DDAH2-EPCs could reduce plaque size and ameliorate endothelial dysfunction in an atherosclerosis rabbit model. METHOD Four groups of rabbits (n = 8 per group) were subjected to a hyperlipidemic diet for a month. After establishing the atherosclerosis model, rabbits received 4 × 106 EPC, EPCs expressing DDAH2, through femoral vein injection, or saline (the control group with basic food and the untreated group). One month after transplantation, plaque thickness, endothelial function, oxidative stress, and inflammatory mRNAs, DDAH, and eNOS function were assessed. RESULTS DDAH2-EPCs transplantation (p < 0.05) and EPCs transplantation (p < 0.05) were both associated with a reduction in plaque size compared to the control saline injection. The antiproliferative and antiatherogenic effects of EPCs were further enhanced by the overexpression of DDAH2 (p < 0.05, DDAH2-EPCs vs. EPCs). Furthermore, DDAH2-EPCs transplantation significantly increased endothelium integrity compared to the EPCs transplantation. CONCLUSION Transplantation of EPCs overexpressing DDAH2 may enhance the repair of injured endothelium by reducing inflammation and restoring endothelial function. Therefore, pCMV6-mediated DDAH2 gene-transfected EPCs are a potentially valuable tool for the treatment of atherosclerosis.
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Affiliation(s)
- Sara Shoeibi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elahe Mahdipour
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shabnam Mohammadi
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Moohebati
- Cardiovascular Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yousefzadeh N, Jeddi S, Kashfi K, Ghasemi A. Diabetoporosis: Role of nitric oxide. EXCLI JOURNAL 2021; 20:764-780. [PMID: 34121973 PMCID: PMC8192884 DOI: 10.17179/excli2021-3541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 03/31/2021] [Indexed: 11/29/2022]
Abstract
Diabetoporosis, diabetic-related decreased bone quality and quantity, is one of the leading causes of osteoporotic fractures in subjects with type 2 diabetes (T2D). This is associated with lower trabecular and cortical bone quality, lower bone turnover rates, lower rates of bone healing, and abnormal posttranslational modifications of collagen. Decreased nitric oxide (NO) bioavailability has been reported within the bones of T2D patients and can be considered as one of the primary mechanisms by which diabetoporosis is manifested. NO donors increase trabecular and cortical bone quality, increase the rate of bone formation, accelerate the bone healing process, delay osteoporosis, and decrease osteoporotic fractures in T2D patients, suggesting the potential therapeutic implication of NO-based interventions. NO is produced in the osteoblast and osteoclast cells by three isoforms of NO synthase (NOS) enzymes. In this review, the roles of NO in bone remodeling in the normal and diabetic states are discussed. Also, the favorable effects of low physiological levels of NO produced by endothelial NOS (eNOS) versus detrimental effects of high pathological levels of NO produced by inducible NOS (iNOS) in diabetoporosis are summarized. Available data indicates decreased bone NO bioavailability in T2D and decreased expression of eNOS, and increased expression and activity of iNOS. NO donors can be considered novel therapeutic agents in diabetoporosis.
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Affiliation(s)
- Nasibeh Yousefzadeh
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA
- PhD Program in Biology, City University of New York Graduate Center, New York,NY, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Singh P, O'Toole TE, Conklin DJ, Hill BG, Haberzettl P. Endothelial progenitor cells as critical mediators of environmental air pollution-induced cardiovascular toxicity. Am J Physiol Heart Circ Physiol 2021; 320:H1440-H1455. [PMID: 33606580 PMCID: PMC8260385 DOI: 10.1152/ajpheart.00804.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/26/2021] [Accepted: 02/14/2021] [Indexed: 01/15/2023]
Abstract
Environmental air pollution exposure is a leading cause of death worldwide, and with increasing industrialization and urbanization, its disease burden is expected to rise even further. The majority of air pollution exposure-associated deaths are linked to cardiovascular disease (CVD). Although ample research demonstrates a strong correlation between air pollution exposure and CVD risk, the mechanisms by which inhalation of polluted air affects cardiovascular health are not completely understood. Inhalation of environmental air pollution has been associated with endothelial dysfunction, which suggests that air pollution exposure impacts CVD health by inducing endothelial injury. Interestingly, recent studies demonstrate that air pollution exposure affects the number and function of endothelial progenitor cells (EPCs), subpopulations of bone marrow-derived proangiogenic cells that have been shown to play an essential role in maintaining cardiovascular health. In line with their beneficial function, chronically low levels of circulating EPCs and EPC dysfunction (e.g., in diabetic patients) have been associated with vascular dysfunction, poor cardiovascular health, and increases in the severity of cardiovascular outcomes. In contrast, treatments that improve EPC number and function (e.g., exercise) have been found to attenuate cardiovascular dysfunction. Considering the critical, nonredundant role of EPCs in maintaining vascular health, air pollution exposure-induced impairments in EPC number and function could lead to endothelial dysfunction, consequently increasing the risk for CVD. This review article covers novel aspects and new mechanistic insights of the adverse effects of air pollution exposure on cardiovascular health associated with changes in EPC number and function.
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Affiliation(s)
- Parul Singh
- Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Timothy E O'Toole
- Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Daniel J Conklin
- Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Bradford G Hill
- Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Petra Haberzettl
- Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
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Zhang B, Li D, Liu G, Tan W, Zhang G, Liao J. Impaired activity of circulating EPCs and endothelial function are associated with increased Syntax score in patients with coronary artery disease. Mol Med Rep 2021; 23:321. [PMID: 33760184 PMCID: PMC7974324 DOI: 10.3892/mmr.2021.11960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
It has previously been shown that the number of endothelial progenitor cells (EPCs) is negatively correlated with Syntax score in patients with coronary artery disease (CAD). However, the association between alterations in EPC function and Syntax score is still unknown. The present study evaluated the association between the activity of EPCs as well as endothelial function and Syntax score in patients with CAD and investigated the underlying mechanisms. A total of 60 patients with CAD were enrolled in 3 groups according to Syntax score, and 20 healthy subjects were recruited as the control group. The number and migratory, proliferative and adhesive activities of circulating EPCs were studied. The endothelial function was measured by flow-mediated dilatation (FMD) and the levels of nitric oxide (NO) in plasma or secreted by EPCs were detected. The number and activity of circulating EPCs were lower in patients with a high Syntax score, which was similar to the alteration in FMD. The level of NO in plasma or secreted by EPCs also decreased as Syntax score increased. There was a negative association between FMD or circulating EPCs and Syntax score. A similar association was observed between the levels of NO in plasma or secreted by EPCs and Syntax score. Patients with CAD who had a higher Syntax score exhibited lower EPC numbers or activity and weaker endothelial function, which may be associated with attenuated NO production. These findings provide novel surrogate parameters for evaluation of the severity and complexity of CAD.
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Affiliation(s)
- Bin Zhang
- Department of Cardiovascular Disease, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat‑Sen University, Jiangmen, Guangdong 529030, P.R. China
| | - Dong Li
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat‑Sen University, Jiangmen, Guangdong 529030, P.R. China
| | - Gexiu Liu
- Institute of Hematology, Medical College, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wenfeng Tan
- Department of Cardiovascular Disease, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat‑Sen University, Jiangmen, Guangdong 529030, P.R. China
| | - Gaoxing Zhang
- Department of Cardiovascular Disease, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat‑Sen University, Jiangmen, Guangdong 529030, P.R. China
| | - Jinli Liao
- Division of Emergency Medicine, Department of General Internal Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China
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Wu Y, Ding Y, Ramprasath T, Zou MH. Oxidative Stress, GTPCH1, and Endothelial Nitric Oxide Synthase Uncoupling in Hypertension. Antioxid Redox Signal 2021; 34:750-764. [PMID: 32363908 PMCID: PMC7910417 DOI: 10.1089/ars.2020.8112] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
Abstract
Significance: Hypertension has major health consequences, which is associated with endothelial dysfunction. Endothelial nitric oxide synthase (eNOS)-produced nitric oxide (NO) signaling in the vasculature plays an important role in maintaining vascular homeostasis. Considering the importance of NO system, this review aims to provide a brief overview of the biochemistry of members of NO signaling, including GTPCH1 [guanosine 5'-triphosphate (GTP) cyclohydrolase 1], tetrahydrobiopterin (BH4), and eNOS. Recent Advances: Being NO signaling activators and regulators of eNOS signaling, BH4 treatment is getting widespread attention either as potential therapeutic agents or as preventive agents. Recent clinical trials also support that BH4 treatment could be considered a promising therapeutic in hypertension. Critical Issues: Under conditions of BH4 depletion, eNOS-generated superoxides trigger pathological events. Abnormalities in NO availability and BH4 deficiency lead to disturbed redox regulation causing pathological events. This disturbed signaling influences the development of systemic hypertension as well as pulmonary hypertension. Future Directions: Considering the importance of BH4 and NO to improve the translational significance, it is essential to continue research on this field to manipulate BH4 to increase the efficacy for treating hypertension. Thus, this review also examines the current state of knowledge on the effects of eNOS activators on preclinical models and humans to utilize this information for potential therapy.
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Affiliation(s)
- Yin Wu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA
| | - Ye Ding
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA
| | - Tharmarajan Ramprasath
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA
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Erkens R, Totzeck M, Brum A, Duse D, Bøtker HE, Rassaf T, Kelm M. Endothelium-dependent remote signaling in ischemia and reperfusion: Alterations in the cardiometabolic continuum. Free Radic Biol Med 2021; 165:265-281. [PMID: 33497796 DOI: 10.1016/j.freeradbiomed.2021.01.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Intact endothelial function plays a fundamental role for the maintenance of cardiovascular (CV) health. The endothelium is also involved in remote signaling pathway-mediated protection against ischemia/reperfusion (I/R) injury. However, the transfer of these protective signals into clinical practice has been hampered by the complex metabolic alterations frequently observed in the cardiometabolic continuum, which affect redox balance and inflammatory pathways. Despite recent advances in determining the distinct roles of hyperglycemia, insulin resistance (InR), hyperinsulinemia, and ultimately diabetes mellitus (DM), which define the cardiometabolic continuum, our understanding of how these conditions modulate endothelial signaling remains challenging. It is widely accepted that endothelial cells (ECs) undergo functional changes within the cardiometabolic continuum. Beyond vascular tone and platelet-endothelium interaction, endothelial dysfunction may have profound negative effects on outcome during I/R. In this review, we summarize the current knowledge of the influence of hyperglycemia, InR, hyperinsulinemia, and DM on endothelial function and redox balance, their influence on remote protective signaling pathways, and their impact on potential therapeutic strategies to optimize protective heterocellular signaling.
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Affiliation(s)
- Ralf Erkens
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
| | - Matthias Totzeck
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Germany
| | - Amanda Brum
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Dragos Duse
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
| | - Hans Erik Bøtker
- Department of Cardiology, Institute of Clinical Medicine, Aarhus University Hospital, Denmark
| | - Tienush Rassaf
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Germany
| | - Malte Kelm
- Department of Cardiology, Pulmonology and Angiology Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
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Meyer N, Brodowski L, Richter K, von Kaisenberg CS, Schröder-Heurich B, von Versen-Höynck F. Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro. J Clin Med 2021; 10:E183. [PMID: 33419165 PMCID: PMC7825508 DOI: 10.3390/jcm10020183] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/28/2020] [Accepted: 12/31/2020] [Indexed: 12/15/2022] Open
Abstract
Endothelial dysfunction is a primary feature of several cardiovascular diseases. Endothelial colony-forming cells (ECFCs) represent a highly proliferative subtype of endothelial progenitor cells (EPCs), which are involved in neovascularization and vascular repair. Statins are known to improve the outcome of cardiovascular diseases via pleiotropic effects. We hypothesized that treatment with the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin increases ECFCs' functional capacities and regulates the expression of proteins which modulate endothelial health in a favourable manner. Umbilical cord blood derived ECFCs were incubated with different concentrations of pravastatin with or without mevalonate, a key intermediate in cholesterol synthesis. Functional capacities such as migration, proliferation and tube formation were addressed in corresponding in vitro assays. mRNA and protein levels or phosphorylation of protein kinase B (AKT), endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1), vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin (Eng) were analyzed by real time PCR or immunoblot, respectively. Proliferation, migration and tube formation of ECFCs were enhanced after pravastatin treatment, and AKT- and eNOS-phosphorylation were augmented. Further, expression levels of HO-1, VEGF-A and PlGF were increased, whereas expression levels of sFlt-1 and Eng were decreased. Pravastatin induced effects were reversible by the addition of mevalonate. Pravastatin induces beneficial effects on ECFC function, angiogenic signaling and protein expression. These effects may contribute to understand the pleiotropic function of statins as well as to provide a promising option to improve ECFCs' condition in cell therapy in order to ameliorate endothelial dysfunction.
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Affiliation(s)
- Nadia Meyer
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Lars Brodowski
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
| | - Katja Richter
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Constantin S. von Kaisenberg
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
| | - Bianca Schröder-Heurich
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
| | - Frauke von Versen-Höynck
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany; (N.M.); (L.B.); (K.R.); (B.S.-H.)
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany;
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