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Čiapienė I, Vėžys J, Lesauskaitė V, Matulevičiūtė I, Meškauskaitė U, Skipskis V, Strazdauskas A, Trumbeckaitė S, Bubulis A, Jūrėnas V, Ostaševičius V, Tamakauskas V, Tatarūnas V. Synergistic Effects of Low-Frequency Ultrasound and Therapeutic Agents on Endothelial and Renal Cells: Emphasis on Cell Functionality, Oxidative Stress, and Inflammatory Markers. Pharmaceuticals (Basel) 2025; 18:404. [PMID: 40143180 PMCID: PMC11945135 DOI: 10.3390/ph18030404] [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: 02/12/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Background: Ischemic heart disease remains the leading cause of death worldwide, with coronary microvascular dysfunction (CMD) as a key complication after ST-elevation myocardial infarction (STEMI). Endothelial dysfunction contributes to CMD, impairing vascular tone and increasing inflammation. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) aid vascular health, their efficacy may improve with therapeutic ultrasound, which enhances drug delivery and endothelial response. This study explores the combined effects of ultrasound and pharmacological treatment on the ACE axis and inflammation in endothelial and renal cells. Methods: Human umbilical vein endothelial cells (HUVECs) and human renal proximal tubular epithelial cell line RPTEC/TERT1 were treated with captopril, losartan, and dexamethasone, alone or combined with low-frequency ultrasound (LFU). Cell viability and wound-healing assays assessed cellular function, while nitric oxide (NO) and reactive oxygen species (ROS) assays were used to evaluate redox signaling. Gene expression related to the ACE axis, inflammation, and vascular and renal cell function was analyzed via qPCR. Results: Captopril and losartan combined with LFU improved endothelial cell viability, wound healing, and NO production at various concentrations, whereas only losartan with LFU enhanced cell viability and wound healing in renal cells. Dexamethasone with LFU increased ROS levels and had variable effects on RPTEC/TERT1 cell survival. Gene expression analysis showed that LFU alone reduced pro-inflammatory markers VCAM-1, ICAM-1, and PTGS2 in captopril-treated HUVECs and similarly affected CYP4F2 in losartan-treated HUVECs. LFU also decreased PTGS2 expression at higher dexamethasone concentrations. In RPTEC/TERT1 cells, LFU alone did not impact SGLT2 or GGT1 expression, but captopril with LFU downregulated GGT1, and dexamethasone with LFU upregulated SGLT2 at higher concentrations. Conclusions: This study demonstrates that LFU enhances the effects of RAS inhibitors by promoting NO synthesis and reducing oxidative stress, while its combination with dexamethasone may have variable, potentially cytotoxic effects on renal cells. Gene expression patterns suggest LFU's anti-inflammatory potential and its role in modulating drug efficacy.
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Affiliation(s)
- Ieva Čiapienė
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
| | - Joris Vėžys
- Department of Mechanical Engineering, Faculty of Mechanical Engineering and Design, Kaunas University of Technology, Studentu 56, LT-51424 Kaunas, Lithuania;
| | - Vaiva Lesauskaitė
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
| | - Indrė Matulevičiūtė
- Department of Ophthalmology, Lithuanian University of Health Sciences, Eiveniu 2, LT-50161 Kaunas, Lithuania;
| | - Ugnė Meškauskaitė
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
| | - Vilius Skipskis
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
| | - Arvydas Strazdauskas
- Department of Biochemistry, Faculty of Medicine, Lithuanian University of Health Sciences, Eiveniu 4, LT-50161 Kaunas, Lithuania;
| | - Sonata Trumbeckaitė
- Department of Pharmacognosy, Faculty of Pharmacy, Lithuanian University of Health Sciences, Sukileliu 13, LT-50162 Kaunas, Lithuania;
| | - Algimantas Bubulis
- Institute of Mechatronics, Kaunas University of Technology, Studentu 56, LT-51424 Kaunas, Lithuania; (A.B.); (V.J.); (V.O.)
| | - Vytautas Jūrėnas
- Institute of Mechatronics, Kaunas University of Technology, Studentu 56, LT-51424 Kaunas, Lithuania; (A.B.); (V.J.); (V.O.)
| | - Vytautas Ostaševičius
- Institute of Mechatronics, Kaunas University of Technology, Studentu 56, LT-51424 Kaunas, Lithuania; (A.B.); (V.J.); (V.O.)
| | - Vytenis Tamakauskas
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
| | - Vacis Tatarūnas
- Institute of Cardiology, Lithuanian University of Health Sciences, Sukileliu 15, LT-50103 Kaunas, Lithuania; (I.Č.); (V.L.); (U.M.); (V.S.); (V.T.)
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Kavurma MM, Bursill C, Stanley CP, Passam F, Cartland SP, Patel S, Loa J, Figtree GA, Golledge J, Aitken S, Robinson DA. Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease. Front Cardiovasc Med 2022; 9:1054576. [PMID: 36465438 PMCID: PMC9709122 DOI: 10.3389/fcvm.2022.1054576] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/24/2022] [Indexed: 08/27/2023] Open
Abstract
Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.
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Affiliation(s)
- Mary M. Kavurma
- Heart Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Christina Bursill
- South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
| | | | - Freda Passam
- Heart Research Institute, The University of Sydney, Sydney, NSW, Australia
- Central Clinical School, Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Siân P. Cartland
- Heart Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Sanjay Patel
- Heart Research Institute, The University of Sydney, Sydney, NSW, Australia
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Jacky Loa
- Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Gemma A. Figtree
- Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia
- Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
- The Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, QLD, Australia
| | - Sarah Aitken
- Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia
- Concord Institute of Academic Surgery, Concord Hospital, Sydney, NSW, Australia
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Li Z, Liu Y, Zhang H, Pu Z, Wu X, Li P. Effect of fosinopril on the renal cortex protein expression profile of Otsuka Long-Evans Tokushima Fatty rats. Exp Ther Med 2019; 19:172-182. [PMID: 31853288 PMCID: PMC6909786 DOI: 10.3892/etm.2019.8188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 08/23/2019] [Indexed: 12/21/2022] Open
Abstract
Angiotensin-converting enzyme inhibitors (ACEIs) can reduce urinary protein excretion and postpone the deterioration of renal function. However, the mechanisms of renal protection are not yet fully understood. To investigate the mechanisms of ACEIs in the treatment of diabetic nephropathy (DN), the present study determined the effects of the ACEI fosinopril (FP) on the profiling of renal cortex protein expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats using Long-Evans Tokushima Otsuka (LETO) rats as controls. Urinary protein levels at 24 h were examined using the Broadford method. PAS staining was performed to observe renal histopathological changes. The kidney cortices of OLETF, FP-treated OLETF and LETO rats were examined using soluble and insoluble high-resolution subproteomic analysis methodology at age of 36 and 56 weeks. Differentiated proteins were further confirmed using western blotting analysis. The results demonstrated that FP significantly decreased the glomerulosclerosis index and reduced the 24 h urinary protein excretion of OLETF rats. Additionally, 17 proteins significantly changed following FP-treatment. Amongst these proteins, the abundances of the stress-response protein heat shock protein family A member 9 and the antioxidant glutathione peroxidase 3 were particularly increased. These results indicated that FP ameliorated diabetic renal injuries by inhibiting oxidative stress. In conclusion, the differentially expressed proteins may improve our understanding of the mechanism of ACEIs in the OLETF rats.
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Affiliation(s)
- Zhiguo Li
- Department of Medical Research Center, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Yeqiang Liu
- Department of Endocrinology, Kailuan General Hospital, Tangshan, Hebei 063000, P.R. China
| | - Haojun Zhang
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Zhijie Pu
- Graduate School, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Xuejing Wu
- Graduate School, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia. Angiogenesis 2014; 17:617-30. [PMID: 24414940 DOI: 10.1007/s10456-014-9414-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 01/04/2014] [Indexed: 01/05/2023]
Abstract
The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endothelial cells having a greater angiogenic potential. This study investigated whether there exists a sub-population of cultured endothelial cells with enhanced angiogenic potency in vitro and in vivo. First, endothelial cells that participated in sprouting, and non-sprouting cells, were separately isolated from a 3D fibrin gel sprouting assay. Interestingly, the sprouting cells, when placed back into the same assay, displayed a sevenfold increase in the number of sprouts, as compared to control cells. Angiotensin-converting enzyme (CD143) was significantly down regulated on sprouting cells, as compared to regular endothelial cells. A subset of endothelial cells with low CD143 expression was then prospectively isolated from an endothelial cell culture. Finally, these cells were found to have greater potency in alleviating local ischemia, and restoring regional blood perfusion when transplanted into ischemic hindlimbs, as compared to unsorted endothelial cells. In summary, this study indicates that low expression of CD143 can be used as a biomarker to identify an endothelial cell sub-population that is more capable to drive neovascularization.
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Bovenzi V, Savard M, Morin J, Cuerrier CM, Grandbois M, Gobeil F. Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli. J Cell Physiol 2009; 222:168-76. [PMID: 19780024 DOI: 10.1002/jcp.21933] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity.
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Affiliation(s)
- Veronica Bovenzi
- Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, Canada
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Shang YC, Wang SH, Xiong F, Zhao CP, Peng FN, Feng SW, Li MS, Li Y, Zhang C. Wnt3a signaling promotes proliferation, myogenic differentiation, and migration of rat bone marrow mesenchymal stem cells. Acta Pharmacol Sin 2007; 28:1761-74. [PMID: 17959027 DOI: 10.1111/j.1745-7254.2007.00671.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
AIM To investigate the effects of the wingless-related MMTV integration site 3A (Wnt3a) signaling on the proliferation, migration, and the myogenic and adipogenic differentiation of rat bone marrow mesenchymal stem cells (rMSC). METHODS Primary MSC were isolated and cultured from Sprague-Dawley rats and characterized by flow cytometry. Mouse L cells were transfected with Wnt3a cDNA, and conditioned media containing active Wnt3a proteins were prepared. Cell proliferation was evaluated by cell count and 5-bromodeoxyuridine incorporation assay. The migration of rMSC was performed by using a transwell migration and wound healing assay. The myogenic and adipogenic differentiation in rMSC were examined by light microscopy, immunofluorescence, and RT-PCR at different time points after myogenic or adipogenic introduction. RESULTS Wnt3a signaling induced beta-catenin nuclear translocation and activated the Wnt pathway in rMSC. In the presence of Wnt3a, rMSC proliferated more rapidly than the control cells, keeping their differentiation potential. Moreover, Wnt3a signaling induced 2.62% and 3.76% of rMSC-expressed desmin and myosin heavy chain after being cultured in myogenic medium. The myogenic differentiation genes, including Pax7, MyoD, Myf5, Myf4, and myogenin, were activated after Wnt3a treatment. On the other hand, Wnt3a inhibited the adipogenic differentiation in rMSC through the downregulated expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma). Furthermore, Wnt3a promoted the migration capacity of rMSC. CONCLUSION The results indicate that Wnt3a signaling can induce myogenic differentiation in rMSC. Wnt3a signaling is also involved in the regulation of the proliferation and migration of rMSC. These results could provide a rational foundation for cell-based tissue repair in humans.
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Affiliation(s)
- Yan-chang Shang
- Department of Neurology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
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He X, Han B, Mura M, Xia S, Wang S, Ma T, Liu M, Liu Z. Angiotensin-converting enzyme inhibitor captopril prevents oleic acid-induced severe acute lung injury in rats. Shock 2007; 28:106-11. [PMID: 17510605 DOI: 10.1097/shk.0b013e3180310f3a] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Lack of specific and efficient therapy leads to the high mortality rate of acute lung injury (ALI) and acute respiratory distress (ARDS). Recent evidence implies that angiotensin-converting enzyme (ACE) plays an important role in the pathogenesis of ALI. Pharmaceutical inhibitors of ACE have been used clinically for hypertension but not for ALI/ARDS yet. The objective was to study the effects of ACE inhibition with captopril on severe lung injury induced by oleic acid (OA) in rats. Oleic acid was intravenously injected into Sprague Dawley rats, followed by i.p. administration of captopril or saline control. Lung injury, endothelium damage and related molecules, and disturbance of coagulation were examined in comparison between the treated and the nontreated groups. An OA-induced ALI was featured with thickening of the alveolar septa, alveolar hemorrhage, and infiltration of inflammatory cells. Comparing with the nontreated OA group, the administration of captopril prevented the rats from OA-induced severe lungs injury, with a significantly lower lung injury score, less albumin content and infiltrated cells in the alveoli, decreased wet/dry weight ratio of the lung tissues, and improved lung function (PaO2 per fraction of inspired oxygen). Captopril also dramatically reduced the expression of intercellular adhesion molecule-1 in the lung tissue and in the circulating endothelial cells in the blood, indicating a protective effect on endothelial cells activation/damage. Moreover, captopril treatment led to a blockage of nuclear factor kappaB activation in lung tissues and to the recovery of the fibrinolytic disturbance. Thus, our data suggest that the inhibition of ACE with its clinically used inhibitor offers protective effects on ALI/ARDS, implying the potential for therapeutic option.
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Affiliation(s)
- Xiaolin He
- Department of Emergency and Institute of Respiratory Disease, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
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Tufan H, Zaki BM, Tecder-Unal M, Erdem SR, Take G. Angiotensin II Captopril Cotreatment Augments Angiogenesis in Abdominal Skin Flap in Rats. Ann Plast Surg 2007; 58:441-8. [PMID: 17413889 DOI: 10.1097/01.sap.0000241682.42511.07] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The effect of captopril, angiotensin-converting enzyme inhibitor, on angiogenesis in several reports remained unclear. Its effect on neovascularization in rat abdominal skin flaps was investigated. Flap elevation, based on the right superficial inferior epigastric artery was performed with or without the administration of captopril (10 mg/kg/d), Ang II (100 microg/kg/d), or captopril and Ang II cotreatment. Mean arterial pressure (MAP), microangiography, capillary density measurement, necrosis area determination, laser Doppler flowmetry (LDF), AT1 and vascular endothelial growth factor (VEGF) immunostaining were used to evaluate the effects of captopril and the interaction between captopril and Ang II on the angiogenesis. Ang II and captopril cotreatment improved angiogenesis more than Ang II or captopril alone. The reduction of necrosis, enhancement of vascular network formation, capillary density, VEGF immunostaining, and local blood flow were evident in the cotreated group. We suggest that Ang II and captopril cotreatment improves ischemia-induced angiogenesis and increased viability and vascularity of skin flap in rats.
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Affiliation(s)
- Hale Tufan
- Başkent University, Faculty of Medicine, Department of Pharmacology, Ankara, Turkey.
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Gálvez AS, Fiedler JL, Ocaranza MP, Jalil JE, Lavandero S, Díaz-Araya G. Perindopril regulates beta-agonist-induced cardiac apoptosis. J Cardiovasc Pharmacol 2006; 46:255-61. [PMID: 16116328 DOI: 10.1097/01.fjc.0000175234.95831.3e] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Administration of the beta-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term beta-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin I-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. beta-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the beta-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P<0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
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Affiliation(s)
- Anita S Gálvez
- Departamento de Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, and Departamento de Enfermedades Cardiovasculares, Hospital Clínico, P. Universidad Católica de Chile, Santiago, Chile
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Yue SQ, Yang YL, Zhou JS, Li KZ, Dou KF. Relationship between urokinase-type plasminogen activator receptor and vascular endothelial growth factor expression and metastasis of gallbladder cancer. World J Gastroenterol 2004; 10:2750-2. [PMID: 15309734 PMCID: PMC4572208 DOI: 10.3748/wjg.v10.i18.2750] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the relationship of urokinase type plasminogen activator receptor (uPAR) and vascular endothelial growth factor (VEGF) expression with clinical and pathological characteristics of human gallbladder cancer.
METHODS: uPAR and VEGF expressions in 68 gallbladder cancer tissues were detected with anti-receptor immunohistochemical stain.
RESULTS: Expression rate of uPAR was 57.4% (39/68), and VEGF 51.5% (35/68) in gallbladder cancer tissues. Expression of both uPAR and VEGF was significantly related to metastasis, but not significantly correlated with differentiation stage and size of gallbladder cancer.
CONCLUSION: Expression of uPAR and VEGF may be an invasive phenotype of gallbladder cancer and indicator for predicting prognoses, and uPAR expression is significantly correlated with the expression of VEGF.
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Affiliation(s)
- Shu-Qiang Yue
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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Hamdi HK, Castellon R. A genetic variant of ACE increases cell survival: a new paradigm for biology and disease. Biochem Biophys Res Commun 2004; 318:187-91. [PMID: 15110771 DOI: 10.1016/j.bbrc.2004.04.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2004] [Indexed: 10/26/2022]
Abstract
The human angiotensin converting enzyme (ACE) polymorphism is caused by an Alu element insertion resulting in three genotypes (Alu+/+, Alu+/-, Alu-/-, or ACE-II, ACE-ID, and ACE-DD, respectively), with ACE-II displaying lower ACE activity. The polymorphism is associated with athletic performance, aging, and disease. Population studies, however, were confounding because variants of the polymorphism appeared to fortuitously correlate with health and various pathological states. To clarify the functional role of the polymorphism, we studied its direct effect on cell survival. ACE-II (Alu+/+) human endothelial cells (EC) had lower angiotensin-II levels and 20-fold increased viability after slow starvation as compared to ACE-DD cells (Alu-/-). By RT-PCR, only ACE-II cells expressed the pluripotent/stem cell-maintenance factors nanog, numb, and klotho. ACE inhibition by captopril in ACE-DD cells mimicked the ACE-II genotype. These results provide the first evidence of a functional role for a naturally occurring polymorphism, having broad implications for human biology, longevity, and disease.
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Affiliation(s)
- Hamdi K Hamdi
- Department of Ophthalmology, University of California, Irvine, 101 The City Drive Bldg. 55, Room 202, Orange, CA 92868, USA.
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