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Yunes-Leites PS, Sun Y, Martínez-Martínez S, Alfayate Á, Toral M, Méndez-Olivares MJ, Colmenar Á, Torralbo AI, López-Maderuelo D, Mateos-García S, Cornfield DN, Vázquez J, Redondo JM, Campanero MR. Phosphatase-independent activity of smooth-muscle calcineurin orchestrates a gene expression program leading to hypertension. PLoS Biol 2025; 23:e3003163. [PMID: 40367288 DOI: 10.1371/journal.pbio.3003163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 04/15/2025] [Indexed: 05/16/2025] Open
Abstract
Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA) through mechanisms that are not completely understood. Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Here, by employing newly created smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice), we show that Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. Unexpectedly, SMC Cn also played a structural role in the early onset and maintenance of Ang-II-induced hypertension, independently of its known phosphatase activity. Among the signaling pathways activated by Ang-II, Cn signaling is essential in SMCs, as nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a transcriptional program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, we discovered that Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and readily regressed hypertension. Mechanistically, Serpine1 induction was mediated by Smad2 activation via the structural role of Cn. These findings uncover an unexpected role for Cn in vascular pathophysiology and highlight PAI-1 as a potential therapeutic target for hypertension.
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Affiliation(s)
- Paula Sofía Yunes-Leites
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Yilin Sun
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
- Tissue and Organ Homeostais Program, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Sara Martínez-Martínez
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Álvaro Alfayate
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
- Cardiovascular Proteomics Laboratoy, CNIC, Madrid, Spain
| | - Marta Toral
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - María José Méndez-Olivares
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Ángel Colmenar
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Ana Isabel Torralbo
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Dolores López-Maderuelo
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Sergio Mateos-García
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - David N Cornfield
- Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Jesús Vázquez
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
- Cardiovascular Proteomics Laboratoy, CNIC, Madrid, Spain
| | - Juan Miguel Redondo
- Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
- Tissue and Organ Homeostais Program, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Miguel R Campanero
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
- Tissue and Organ Homeostais Program, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
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Khoukaz HB, Vadali M, Schoenherr A, Ramirez-Perez FI, Morales-Quinones M, Sun Z, Fujie S, Foote CA, Lyu Z, Zeng S, Augenreich MA, Cai D, Chen SY, Joshi T, Ji Y, Hill MA, Martinez-Lemus LA, Fay WP. PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol 2024; 44:2191-2203. [PMID: 38868940 PMCID: PMC11424258 DOI: 10.1161/atvbaha.124.320938] [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: 04/09/2024] [Accepted: 06/01/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness. METHODS PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity. RESULTS PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content. CONCLUSIONS PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.
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Affiliation(s)
- Hekmat B Khoukaz
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Manisha Vadali
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Alex Schoenherr
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Francisco I Ramirez-Perez
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Mariana Morales-Quinones
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Zhe Sun
- Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Shumpei Fujie
- Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan (S.F.)
| | - Christopher A Foote
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Zhen Lyu
- Electrical Engineering and Computer Science (Z.L., S.Z.), University of Missouri, Columbia
| | - Shuai Zeng
- Electrical Engineering and Computer Science (Z.L., S.Z.), University of Missouri, Columbia
| | - Marc A Augenreich
- Nutrition and Exercise Physiology (M.A.A.), University of Missouri, Columbia
| | - Dunpeng Cai
- Surgery (D.C., S.-Y.C.), University of Missouri, Columbia
| | - Shi-You Chen
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Surgery (D.C., S.-Y.C.), University of Missouri, Columbia
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (S.-Y.C., W.P.F.)
| | - Trupti Joshi
- Health Management and Informatics (T.J.), University of Missouri, Columbia
| | - Yan Ji
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Michael A Hill
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - Luis A Martinez-Lemus
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
| | - William P Fay
- Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (S.-Y.C., W.P.F.)
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Zhang J, Liu S, Ding W, Wan J, Qin JJ, Wang M. Resolution of inflammation, an active process to restore the immune microenvironment balance: A novel drug target for treating arterial hypertension. Ageing Res Rev 2024; 99:102352. [PMID: 38857706 DOI: 10.1016/j.arr.2024.102352] [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: 11/24/2023] [Revised: 05/11/2024] [Accepted: 05/27/2024] [Indexed: 06/12/2024]
Abstract
The resolution of inflammation, the other side of the inflammatory response, is defined as an active and highly coordinated process that promotes the restoration of immune microenvironment balance and tissue repair. Inflammation resolution involves several key processes, including dampening proinflammatory signaling, specialized proresolving lipid mediator (SPM) production, nonlipid proresolving mediator production, efferocytosis and regulatory T-cell (Treg) induction. In recent years, increasing attention has been given to the effects of inflammation resolution on hypertension. Furthermore, our previous studies reported the antihypertensive effects of SPMs. Therefore, in this review, we aim to summarize and discuss the detailed association between arterial hypertension and inflammation resolution. Additional, the association between gut microbe-mediated immune and hypertension is discussed. This findings suggested that accelerating the resolution of inflammation can have beneficial effects on hypertension and its related organ damage. Exploring novel drug targets by focusing on various pathways involved in accelerating inflammation resolution will contribute to the treatment and control of hypertensive diseases in the future.
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Affiliation(s)
- Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Siqi Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wen Ding
- Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, China; Department of Radiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, China.
| | - Juan-Juan Qin
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Center for Healthy Aging, Wuhan University School of Nursing, Wuhan, China.
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University; Cardiovascular Research Institute, Wuhan University; Hubei Key Laboratory of Cardiology, Wuhan, China.
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Tapia-Castillo A, Carvajal CA, Pérez JA, Sandoval A, Allende F, Solari S, Fardella CE. Low Cortisone as a Novel Predictor of the Low-Renin Phenotype. J Endocr Soc 2024; 8:bvae051. [PMID: 38586159 PMCID: PMC10998281 DOI: 10.1210/jendso/bvae051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Indexed: 04/09/2024] Open
Abstract
A large proportion of patients with low-renin hypertension (LRH) correspond to primary aldosteronism (PA). However, some of these subjects have low to normal aldosterone. Since low renin is driven by excessive mineralocorticoids or glucocorticoids acting on mineralocorticoid receptors (MRs), we hypothesize that a low-cortisone condition, associated classically with 11βHSD2 deficiency, is a proxy of chronic MR activation by cortisol, which can also lead to low renin, elevated blood pressure, and renal and vascular alterations. Objective To evaluate low cortisone as a predictor of low renin activity and its association with parameters of kidney and vascular damage. Methods A cross-sectional study was carried out in 206 adult subjects. The subjects were classified according to low plasma renin activity (<1 ng/mL × hours) and low cortisone (<25th percentile). Results Plasma renin activity was associated with aldosterone (r = 0.36; P < .001) and cortisone (r = 0.22; P = .001). A binary logistic regression analysis showed that serum cortisone per ug/dL increase predicted the low-renin phenotype (OR 0.4, 95% CI 0.21-0.78). The receiver operating characteristic curves for cortisone showed an area under the curve of 0.6 to discriminate subjects with low renin activity from controls. The low-cortisone subjects showed higher albuminuria and PAI-1 and lower sodium excretion. The association study also showed that urinary cortisone was correlated with blood pressure and serum potassium (P < .05). Conclusion This is the first study showing that low cortisone is a predictor of a low-renin condition. Low cortisone also predicted surrogate markers of vascular and renal damage. Since the aldosterone to renin ratio is used in the screening of PA, low cortisone values should be considered additionally to avoid false positives in the aldosterone-renin ratio calculation.
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Affiliation(s)
- Alejandra Tapia-Castillo
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Centro Traslacional de Endocrinología UC (CETREN-UC), Santiago 8330033, Chile
| | - Cristian A Carvajal
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Centro Traslacional de Endocrinología UC (CETREN-UC), Santiago 8330033, Chile
| | - Jorge A Pérez
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Centro Traslacional de Endocrinología UC (CETREN-UC), Santiago 8330033, Chile
| | - Alejandra Sandoval
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Centro Traslacional de Endocrinología UC (CETREN-UC), Santiago 8330033, Chile
| | - Fidel Allende
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Sandra Solari
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Carlos E Fardella
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Centro Traslacional de Endocrinología UC (CETREN-UC), Santiago 8330033, Chile
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Hua R, Gao H, He C, Xin S, Wang B, Zhang S, Gao L, Tao Q, Wu W, Sun F, Xu J. An emerging view on vascular fibrosis molecular mediators and relevant disorders: from bench to bed. Front Cardiovasc Med 2023; 10:1273502. [PMID: 38179503 PMCID: PMC10764515 DOI: 10.3389/fcvm.2023.1273502] [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: 08/06/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Vascular fibrosis is a widespread pathologic condition that arises during vascular remodeling in cardiovascular dysfunctions. According to previous studies, vascular fibrosis is characterized by endothelial matrix deposition and vascular wall thickening. The RAAS and TGF-β/Smad signaling pathways have been frequently highlighted. It is, however, far from explicit in terms of understanding the cause and progression of vascular fibrosis. In this review, we collected and categorized a large number of molecules which influence the fibrosing process, in order to acquire a better understanding of vascular fibrosis, particularly of pathologic dysfunction. Furthermore, several mediators that prevent vascular fibrosis are discussed in depth in this review, with the aim that this will contribute to the future prevention and treatment of related conditions.
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Affiliation(s)
- Rongxuan Hua
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Han Gao
- Department of Clinical Laboratory, Aerospace Center Hospital, Peking University, Beijing, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shuzi Xin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Boya Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China
| | - Sitian Zhang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Gao
- Department of Biomedical Informatics, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Qiang Tao
- Department of Biomedical Informatics, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Wenqi Wu
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing, China
| | - Fangling Sun
- Department of Experimental Animal Laboratory, Xuan-Wu Hospital of Capital Medical University, Beijing, China
| | - Jingdong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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Ma J, Li Y, Yang X, Liu K, Zhang X, Zuo X, Ye R, Wang Z, Shi R, Meng Q, Chen X. Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:168. [PMID: 37080965 PMCID: PMC10119183 DOI: 10.1038/s41392-023-01430-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/03/2023] [Accepted: 03/31/2023] [Indexed: 04/22/2023] Open
Abstract
Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.
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Affiliation(s)
- Jun Ma
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Yanan Li
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xiangyu Yang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Kai Liu
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xin Zhang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xianghao Zuo
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Runyu Ye
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ziqiong Wang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Rufeng Shi
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Qingtao Meng
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Xiaoping Chen
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
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Rafaqat S, Nasreen S, Rafaqat S. Role of major adipokines in hypertension: A literature review. World J Hypertens 2023; 11:1-11. [DOI: 10.5494/wjh.v11.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/11/2023] [Accepted: 03/06/2023] [Indexed: 03/20/2023] Open
Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Sobia Nasreen
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Sana Rafaqat
- Department of Biotechnology, Lahore College for Women University, Lahore 54000, Pakistan
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Catarinella G, Nicoletti C, Bracaglia A, Procopio P, Salvatori I, Taggi M, Valle C, Ferri A, Canipari R, Puri PL, Latella L. SerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson-Gilford progeria syndrome. Cell Death Dis 2022; 13:737. [PMID: 36028501 PMCID: PMC9418244 DOI: 10.1038/s41419-022-05168-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 01/21/2023]
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of peripheral heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. Yet, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. A genome-wide analysis of gene expression in cultures of primary HGPS fibroblasts identified SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1), as central gene that propels a cell-autonomous pathogenic signaling from the altered nuclear lamina. Indeed, siRNA-mediated downregulation and pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by the correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector and target for therapeutic interventions in HGPS pathogenesis.
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Affiliation(s)
| | - Chiara Nicoletti
- grid.479509.60000 0001 0163 8573Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA
| | - Andrea Bracaglia
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.6530.00000 0001 2300 0941PhD Program in Cellular and Molecular Biology, Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Paola Procopio
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.10253.350000 0004 1936 9756Present Address: BPC, Pharmakologisches Institut, Philipps-Universität Marburg, Marburg, Germany
| | - Illari Salvatori
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.7841.aDepartment of Experimental Medicine, University of Rome “La Sapienza”, 00161 Rome, Italy
| | - Marilena Taggi
- grid.7841.aDAHFMO, Unit of Histology and Medical Embryology, Sapienza, University of Rome, Rome, Italy
| | - Cristiana Valle
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.5326.20000 0001 1940 4177Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
| | - Alberto Ferri
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.5326.20000 0001 1940 4177Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
| | - Rita Canipari
- grid.7841.aDAHFMO, Unit of Histology and Medical Embryology, Sapienza, University of Rome, Rome, Italy
| | - Pier Lorenzo Puri
- grid.479509.60000 0001 0163 8573Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA
| | - Lucia Latella
- grid.417778.a0000 0001 0692 3437IRCCS Fondazione Santa Lucia, Rome, Italy ,grid.5326.20000 0001 1940 4177Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
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9
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Honda M, Tsuboi A, Minato-Inokawa S, Takeuchi M, Kurata M, Yamamoto A, Hirota Y, Wu B, Kazumi T, Fukuo K. Elevated Blood Pressure (≥120/80 mmHg) Is Associated with Elevated Serum Plasminogen Activator Inhibitor-1, Low Birth Weight, and Family History of Diabetes in Young Normal Weight Japanese Women. Metab Syndr Relat Disord 2021; 20:88-93. [PMID: 34978864 DOI: 10.1089/met.2021.0071] [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: 11/13/2022] Open
Abstract
Objective: We examined whether elevated blood pressure (BP) (≥120/80 mmHg) was associated with several anthropometric, metabolic, and clinical variables, including the family history of type 2 diabetes (FHD) and low birth weight, in young normal weight Japanese women. Methods: BP, body composition, and fasting glucose, insulin, lipids, lipoproteins, apolipoproteins, and adipokines were measured in 332 young Japanese women. They received a questionnaire on birth weight and FHD. Results: The prevalence of low birth weight was 2.4% and that of positive FHD was 22.9%. Homeostasis model assessment-insulin resistance averaged <1.5 and did not differ cross-sectionally between 32 women with elevated BP and 300 women with normal BP although mean body mass index was higher in the former than in the latter (21.7 ± 2.9 kg/m2 vs. 20.8 ± 2.2 kg/m2, P = 0.02). Women with elevated BP had higher fat mass index (P = 0.02) and trunk fat percentage (P = 0.04). They had lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 (both P = 0.01) while fasting triglycerides and apolipoprotein B did not differ. In addition, they had higher plasminogen activator inhibitor-1 (PAI-1) (P = 0.001). Furthermore, the prevalence of low birth weight (9.4% vs. 1.7%, P = 0.03) and positive FHD (40.6% vs. 20.0%, P = 0.01) was higher in women with elevated BP. Multivariable logistic regression analyses revealed that elevated BP was independently associated with PAI-1 [odds ratio (OR); 1.05, 95% confidence interval (CI): 1.02-1.08, P = 0.001], low birth weight (OR: 12.3, 95% CI: 2.3-67.3, P = 0.04), and FHD (OR: 3.0, 95% CI: 1.3-7.9, P = 0.01). Conclusion: Elevated BP was associated with positive FHD, low birth weight, and elevated serum PAI-1 in young normal weight Japanese women.
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Affiliation(s)
- Mari Honda
- Open Research Center for Studying of Lifestyle-Related Diseases, Mukogawa Women's University, Nishinomiya, Japan.,Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women's University, Kobe, Japan
| | - Ayaka Tsuboi
- Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan.,Department of Nutrition, Osaka City Juso Hospital, Osaka, Japan
| | - Satomi Minato-Inokawa
- Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan.,Laboratory of Community Health and Nutrition, Department of Bioscience, Graduate School of Agriculture, Ehime University, Matsuyama, Japan
| | - Mika Takeuchi
- Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan
| | - Miki Kurata
- Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan.,Department of Food Sciences and Nutrition, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Japan
| | - Akane Yamamoto
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Bin Wu
- Open Research Center for Studying of Lifestyle-Related Diseases, Mukogawa Women's University, Nishinomiya, Japan.,Department of Endocrinology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tsutomu Kazumi
- Open Research Center for Studying of Lifestyle-Related Diseases, Mukogawa Women's University, Nishinomiya, Japan.,Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan.,Department of Medicine, Kohnan Kakogawa Hospital, Kakogawa, Japan
| | - Keisuke Fukuo
- Open Research Center for Studying of Lifestyle-Related Diseases, Mukogawa Women's University, Nishinomiya, Japan.,Research Institute for Nutrition Sciences, Mukogawa Women's University, Nishinomiya, Japan.,Department of Food Sciences and Nutrition, School of Food Sciences and Nutrition, Mukogawa Women's University, Nishinomiya, Japan
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10
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Morrow GB, Whyte CS, Mutch NJ. A Serpin With a Finger in Many PAIs: PAI-1's Central Function in Thromboinflammation and Cardiovascular Disease. Front Cardiovasc Med 2021; 8:653655. [PMID: 33937363 PMCID: PMC8085275 DOI: 10.3389/fcvm.2021.653655] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/23/2021] [Indexed: 12/27/2022] Open
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a member of the serine protease inhibitor (serpin) superfamily. PAI-1 is the principal inhibitor of the plasminogen activators, tissue plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Turbulence in the levels of PAI-1 tilts the balance of the hemostatic system resulting in bleeding or thrombotic complications. Not surprisingly, there is strong evidence that documents the role of PAI-1 in cardiovascular disease. The more recent uncovering of the coalition between the hemostatic and inflammatory pathways has exposed a distinct role for PAI-1. The storm of proinflammatory cytokines liberated during inflammation, including IL-6 and TNF-α, directly influence PAI-1 synthesis and increase circulating levels of this serpin. Consequently, elevated levels of PAI-1 are commonplace during infection and are frequently associated with a hypofibrinolytic state and thrombotic complications. Elevated PAI-1 levels are also a feature of metabolic syndrome, which is defined by a cluster of abnormalities including obesity, type 2 diabetes, hypertension, and elevated triglyceride. Metabolic syndrome is in itself defined as a proinflammatory state associated with elevated levels of cytokines. In addition, insulin has a direct impact on PAI-1 synthesis bridging these pathways. This review describes the key physiological functions of PAI-1 and how these become perturbed during disease processes. We focus on the direct relationship between PAI-1 and inflammation and the repercussion in terms of an ensuing hypofibrinolytic state and thromboembolic complications. Collectively, these observations strengthen the utility of PAI-1 as a viable drug target for the treatment of various diseases.
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Affiliation(s)
- Gael B Morrow
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.,Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Claire S Whyte
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
| | - Nicola J Mutch
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
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11
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Albhaisi S, Noureddin M. Current and Potential Therapies Targeting Inflammation in NASH. Front Endocrinol (Lausanne) 2021; 12:767314. [PMID: 34925237 PMCID: PMC8678040 DOI: 10.3389/fendo.2021.767314] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD). It is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. Inflammation plays a key role in the progression of NASH and can be provoked by intrahepatic (e.g., lipotoxicity, immune responses, oxidative stress and cell death) and extrahepatic sources (adipose tissue or gut). The identification of triggers of inflammation is central to understanding the mechanisms in NASH development and progression and in designing targeted therapies that can halt or reverse the disease. In this review, we summarize the current and potential therapies targeting inflammation in NASH.
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Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
- *Correspondence: Somaya Albhaisi,
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, CA, United States
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12
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Olivares S, Henkel AS. Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis. FASEB Bioadv 2020; 2:695-704. [PMID: 33336157 PMCID: PMC7734423 DOI: 10.1096/fba.2020-00056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/19/2020] [Accepted: 08/25/2020] [Indexed: 01/20/2023] Open
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a stress-responsive gene that is highly induced in nonalcoholic steatohepatitis (NASH). Endoplasmic reticulum (ER) stress is a salient feature of NASH, yet it is unknown whether ER stress contributes to hepatic PAI-1 induction in this disorder. Therefore, we aimed to (a) establish the role of ER stress in the regulation of hepatic Pai-1 expression, and (b) determine whether induction of Pai-1 in murine NASH is driven by ER stress. Hepatic Pai-1 expression was measured in C57BL/6 J mice and human HepG2 cells subjected to acute or prolonged pharmacologic ER stress. We found that hepatic Pai-1 expression was acutely suppressed in murine liver in response to severe ER stress followed by marked induction during the recovery phase of the ER stress response. Hepatic Pai-1 expression was induced in response to prolonged low-grade ER stress in mice. Induction of PAI-1 by ER stress in HepG2 cells was prevented by pharmacologic inhibition of MEK1/ERK signaling or by siRNA-mediated knockdown of XBP1, mediators of the recovery response to ER stress. Inhibiting ER stress with 4-phenylbutyric acid prevented hepatic Pai-1 induction in mice with diet-induced steatohepatitis. We conclude that hepatic Pai-1 is induced by ER stress via a pathway involving XBP1 and MEK1/ERK signaling, and induction of hepatic Pai-1 in murine NASH is mediated by ER stress. These data implicate ER stress as a novel mechanistic link between Pai-1 induction and NASH.
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Affiliation(s)
- Shantel Olivares
- Department of MedicineNorthwestern UniversityChicagoILUSA
- Jesse Brown VA Medical CenterChicagoILUSA
| | - Anne S. Henkel
- Department of MedicineNorthwestern UniversityChicagoILUSA
- Jesse Brown VA Medical CenterChicagoILUSA
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13
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Lu SL, Huang CF, Li CL, Lu HK, Chen LS. Role of IL-6 and STAT3 signaling in dihydropyridine-induced gingival overgrowth fibroblasts. Oral Dis 2020; 27:1796-1805. [PMID: 33200478 DOI: 10.1111/odi.13724] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 10/06/2020] [Accepted: 11/02/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVES This study analyzed the role of the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) pathway in dihydropyridine-induced gingival overgrowth (DIGO) fibroblasts. MATERIALS AND METHODS Tissue samples were obtained through surgical dissection from five DIGO patients and five healthy individuals. Cell cultures were conditioned with nifedipine (Nif) (0.34 µM) and stimulated with IL-1β (10 ng/ml) to clarify whether IL-6 upregulates extracellular matrix overproduction or has an impact on the cell proliferation rate of DIGO fibroblasts. STAT3 was knocked down using short hairpin (sh)RNA to determine its role in collagen (Col) type I alpha 1 (Colα1(I)) synthesis. RESULTS Results showed that phosphorylated (p)STAT3 nuclear translocation was activated by a simulated autocrine concentration (50 ng/ml) of IL-6, and application of an anti-IL-6 antibody significantly decreased the pSTAT3/STAT3 ratio in DIGO fibroblasts. STAT3 knockdown significantly decreased STAT3 and Colα1(I) expressions in DIGO cells. DIGO tissues presented stronger proliferating cell nuclear antigen (PCNA) expression than did healthy individuals under the effect of IL-1β/Nif treatment. CONCLUSIONS Gingival inflammation (e.g., IL-1β) and taking dihydropyridine (e.g., Nif) may additively stimulate Col overproduction through the IL-6-STAT3-Colα1(I) cascade in DIGO cells. IL-6-STAT3 signaling may be considered a target for the control of DIGO.
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Affiliation(s)
- Sao-Lun Lu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chiung-Fang Huang
- Division of Family and Operative Dentistry, Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan.,School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chuan-Li Li
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsein-Kun Lu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.,Periodontal Clinic, Dental Department, Taipei Medical University Hospital, Taipei, Taiwan
| | - Li-Sheng Chen
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
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14
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Long MT, Gandhi S, Loomba R. Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154259. [PMID: 32387227 PMCID: PMC7529729 DOI: 10.1016/j.metabol.2020.154259] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/29/2020] [Accepted: 05/01/2020] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease in the United States, affecting approximately 1 out of every 4 Americans. NAFLD is a spectrum of disorders including simple steatosis, characterized by the presence of hepatic steatosis with minimal inflammation, and nonalcoholic steatohepatitis (NASH), characterized by the presence of hepatic steatosis with lobular inflammation, ballooning with or without peri-sinusoidal fibrosis. NASH may lead to progressive fibrosis, and therefore, Individuals with NASH and, in particular, hepatic fibrosis are at increased risk for both liver- and cardiovascular-related outcomes compared to those with steatosis alone. New treatments for NASH and hepatic fibrosis are emerging, so now, more than ever, it is important to identify individuals with more advanced disease who may be candidates for therapy. Noninvasive methods to accurately diagnosis, risk stratify, and monitor both NASH and fibrosis are critically needed. Moreover, since clinically relevant outcomes, such as developing end stage liver disease or liver cancer, take many years to develop, reliable surrogate markers of outcome measures are needed to identify and evaluate potential therapies. In this review, we discuss methods to noninvasively diagnosis and monitor both NASH and fibrosis.
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Affiliation(s)
- Michelle T Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, United States of America.
| | - Sanil Gandhi
- Boston University, Boston, MA, United States of America
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, United States of America; NAFLD Research Center, University of California at San Diego, La Jolla, CA, United States of America; Division of Epidemiology, Department of Family and Preventive, University of California at San Diego, La Jolla, CA, United States of America.
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15
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Tincopa MA. Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis. Endocrinol Diabetes Metab 2020; 3:e00177. [PMID: 33102798 PMCID: PMC7576258 DOI: 10.1002/edm2.177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/17/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION In the setting of the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease worldwide. Approximately 25% of adults globally have NAFLD which includes those with NAFL, or simple steatosis, and individuals with nonalcoholic steatohepatitis (NASH) where inflammation, hepatocyte injury and potentially hepatic fibrosis are found in conjunction with steatosis. Individuals with NASH, particularly those with hepatic fibrosis, have higher rates of liver-related and overall mortality, making this distinction of significant clinical importance. One of the core challenges in current clinical practice is identifying this subset of individuals with NASH without the use of liver biopsy, the gold standard for both diagnostics and staging disease severity. Identifying noninvasive biomarkers, an accurately measured and reproducible parameter, would aide in identifying patients eligible for NASH pharmacotherapy clinical trials and to help tailor intensity of monitoring required. METHODS RESULTS AND CONCLUSIONS In this review, we highlight both the currently available and novel diagnostic and interventional circulating biomarkers under investigation for NASH, underscoring their accuracy and limitations relevant to our patient population and current clinical practice.
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Affiliation(s)
- Monica A. Tincopa
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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16
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tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β. J Neurosci 2020; 40:8160-8173. [PMID: 32928888 DOI: 10.1523/jneurosci.1140-20.2020] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/29/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023] Open
Abstract
The amyloid-β (Aβ) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Aβ accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Aβ. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11- to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Aβ and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation.SIGNIFICANCE STATEMENT Amyloid-β (Aβ) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Aβ attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Aβ accumulation. The findings demonstrate a previously unappreciated role of tPA in Aβ-related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.
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17
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Plasminogen activator inhibitor-1 activity and the 4G/5G polymorphism are prospectively associated with blood pressure and hypertension status. J Hypertens 2020; 37:2361-2370. [PMID: 31356402 DOI: 10.1097/hjh.0000000000002204] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Plasminogen activator inhibitor-1 (PAI-1) has consistently shown positive associations with blood pressure (BP). Whether elevations in PAI-1 levels precede or result from raised BP is still under debate and data on prospective studies are limited. Hence, we investigated the prospective associations of PAI-1 and the 4G/5G polymorphism with brachial and central BP and pulse pressure (PP) over a 10-year period. METHODS Black South Africans aged 30 years and older were included. Baseline data collection commenced in 2005 (n = 2010) with follow-up data collection in 2010 (n = 1288) and 2015 (n = 926). Plasma PAI-1 activity (PAI-1act), 4G/5G polymorphism genotyping, waist circumference and BP measurements were performed and analysed using sequential regression and mixed models. RESULTS In multivariable adjusted analyses, PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension in the total group [1.04 (1.01; 1.08) and 1.82 (1.07; 3.12) respectively]. Furthermore, PAI-1act was prospectively associated with brachial SBP (r = 0.0815) and PP (r = 0.0832) in the total group, and with central PP in women (r = 0.1125; all P < 0.05). Addition of waist circumference to the models either decreased or nullified the contribution of PAI-1act to BP and hypertension development. CONCLUSION PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension. Furthermore, PAI-1act associated prospectively with both brachial and central BP. These associations were mediated in part by central adiposity. The study supports the hypothesis that PAI-1 also contributes to hypertension development rather than solely being a consequence thereof.
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18
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Patel S, Dushenkov A, Jungsuwadee P, Krishnaswami A, Barac A. Team-Based Approach to Management of Hypertension Associated with Angiogenesis Inhibitors. J Cardiovasc Transl Res 2020; 13:463-477. [PMID: 32430701 DOI: 10.1007/s12265-020-10024-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/05/2020] [Indexed: 12/28/2022]
Abstract
Angiogenesis inhibitors, also known as vascular endothelial growth factor (VEGF) or vascular signaling pathway (VSP) inhibitors, have improved care of neoplastic diseases over the past decade. However, cardiovascular toxicities associated with these agents, such as hypertension and less commonly left ventricular systolic dysfunction and heart failure, have often been a limiting factor for continued use. Balancing the benefits of these agents with the associated toxicities is critical to ensure these therapies do not negatively impact oncological outcomes. The care of cancer patients with cardiovascular risks is challenging due to the heterogeneity of cardiovascular complications, paucity of evidence-based guidelines, and lack of channels for collaboration among healthcare providers. Herein, we provide a team-based approach for treatment of angiogenesis inhibitor-induced hypertension along with recommendations on monitoring and appropriate selection of anti-hypertensive agents.
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Affiliation(s)
- Shreya Patel
- Division of Pharmacy Practice, School of Pharmacy and Health Sciences, Fairleigh Dickinson University, 230 Park Avenue, Florham Park, NJ, 07932, USA.
| | - Anna Dushenkov
- Division of Pharmacy Practice, School of Pharmacy and Health Sciences, Fairleigh Dickinson University, 230 Park Avenue, Florham Park, NJ, 07932, USA
| | - Paiboon Jungsuwadee
- Division of Pharmaceutical Sciences, School of Pharmacy and Health Sciences, Fairleigh Dickinson University, Florham Park, NJ, USA
| | - Ashok Krishnaswami
- Division of Cardiology, Kaiser Permanente San Jose Medical Center, San Jose, CA, USA
| | - Ana Barac
- MedStar Heart and Vascular Institute, Washington, DC, USA
- Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
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19
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Garcia V, Park EJ, Siragusa M, Frohlich F, Mahfuzul Haque M, Pascale JV, Heberlein KR, Isakson BE, Stuehr DJ, Sessa WC. Unbiased proteomics identifies plasminogen activator inhibitor-1 as a negative regulator of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 2020; 117:9497-9507. [PMID: 32300005 PMCID: PMC7196906 DOI: 10.1073/pnas.1918761117] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a critical mediator of vascular function. eNOS is tightly regulated at various levels, including transcription, co- and posttranslational modifications, and by various protein-protein interactions. Using stable isotope labeling with amino acids in cell culture (SILAC) and mass spectrometry (MS), we identified several eNOS interactors, including the protein plasminogen activator inhibitor-1 (PAI-1). In cultured human umbilical vein endothelial cells (HUVECs), PAI-1 and eNOS colocalize and proximity ligation assays demonstrate a protein-protein interaction between PAI-1 and eNOS. Knockdown of PAI-1 or eNOS eliminates the proximity ligation assay (PLA) signal in endothelial cells. Overexpression of eNOS and HA-tagged PAI-1 in COS7 cells confirmed the colocalization observations in HUVECs. Furthermore, the source of intracellular PAI-1 interacting with eNOS was shown to be endocytosis derived. The interaction between PAI-1 and eNOS is a direct interaction as supported in experiments with purified proteins. Moreover, PAI-1 directly inhibits eNOS activity, reducing NO synthesis, and the knockdown or antagonism of PAI-1 increases NO bioavailability. Taken together, these findings place PAI-1 as a negative regulator of eNOS and disruptions in eNOS-PAI-1 binding promote increases in NO production and enhance vasodilation in vivo.
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Affiliation(s)
- Victor Garcia
- Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520
| | - Eon Joo Park
- Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520
| | - Mauro Siragusa
- Institute for Vascular Signaling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany
| | - Florian Frohlich
- Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520
- Department of Biology/Chemistry, Molecular Membrane Biology Section, University of Osnabrück, 49076 Osnabrück, Germany
| | - Mohammad Mahfuzul Haque
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Jonathan V Pascale
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595
| | - Katherine R Heberlein
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908
| | - Dennis J Stuehr
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - William C Sessa
- Vascular Biology and Therapeutics Program, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
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20
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Morsy MD. Hemostatic effect of acylated ghrelin in control and sleeve gastrectomy-induced rats: mechanisms of action. Arch Physiol Biochem 2020; 126:31-40. [PMID: 30320517 DOI: 10.1080/13813455.2018.1489849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
This study investigated the effect of acylated ghrelin (AG) deficiency after sleeve gastrectomy (SG) or chronic administration in control and SG-indiuced rats on platelet function, coagulation, and fibrinolysis. Administration of AG (100 µg/kg, subcutaneously) to control or SG rats significantly inhibited platelets aggregation and lowered levels of Von-Willebrand factor (vWF), fibrinogen, and thromboxane B2. Concomitantly, it decreased circulatory levels and aortic expression levels of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) and increased the aortic expression of the endothelial nitric oxidase (eNOS). However, AG inhibited angiotensin-II (ANGII)-induced upregulation of tissue factor pathway inhibitor (TPAI) and TF and increased activity of TF and increases eNOS expression in cultured endothelial cells, an effect that was abolished by the addition of D-[lys3]-GHRP-6, a selective AG receptor (GHSR-1a) blocker or L-Name, a potent eNOS inhibitor. In conclusion, AG has an anti-platelet, anti-coagulant, and fibrinolytic roles mediated through GHSR-1a to enhance nitric oxide synthesis.
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Affiliation(s)
- Mohamed Darwesh Morsy
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Physiology, College of Medicine, Menoufia University, Shebeen Alkoom, Egypt
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21
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Khan MS, Yamashita K, Sharma V, Ranjan R, Selzman CH, Dosdall DJ. Perioperative Biomarkers Predicting Postoperative Atrial Fibrillation Risk After Coronary Artery Bypass Grafting: A Narrative Review. J Cardiothorac Vasc Anesth 2019; 34:1933-1941. [PMID: 31653497 DOI: 10.1053/j.jvca.2019.09.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/06/2019] [Accepted: 09/12/2019] [Indexed: 12/11/2022]
Abstract
Postoperative atrial fibrillation (POAF) after cardiac surgery remains a highly prevalent and costly condition that negatively impacts patient quality of life and survival. Numerous retrospective studies, meta-analysis, and review papers have been reported identifying POAF risk based on patients' risk factors and clinical biomarkers. In this narrative review, the authors report significant variations among selected pre- and perioperative biomarkers used to predict POAF incidence in patients without a history of atrial fibrillation (AF). POAF prediction based on B-type natriuretic peptide, N-terminal pro B-type natriuretic peptide, C-reactive protein, interleukin-6, creatinine, and plasminogen activator inhibitor-1 differs significantly among different studies, thereby limiting their clinical utility to predict POAF risk with high accuracy. Conversely, soluble vascular endothelial cells adhesion molecule-1, soluble CD40 ligand, Galectin-3, and aldosterone show promise for better POAF prediction. However, the current datasets for these selected biomarkers are not of sufficient size to validate the broad clinical application specifically for patients with no prior history of AF.
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Affiliation(s)
- Muhammad S Khan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT
| | - Kennosuke Yamashita
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT; Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT
| | - Vikas Sharma
- Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT
| | - Ravi Ranjan
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT; Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT; Department of Bioengineering, University of Utah, Salt Lake City, UT
| | - Craig H Selzman
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT; Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT
| | - Derek J Dosdall
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT; Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT; Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT; Department of Bioengineering, University of Utah, Salt Lake City, UT.
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22
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Basurto L, Sánchez L, Díaz A, Valle M, Robledo A, Martínez-Murillo C. Differences between metabolically healthy and unhealthy obesity in PAI-1 level. Thromb Res 2019; 180:110-114. [DOI: 10.1016/j.thromres.2019.06.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/19/2019] [Accepted: 06/20/2019] [Indexed: 12/29/2022]
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23
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del Campo L, Sánchez‐López A, Salaices M, von Kleeck RA, Expósito E, González‐Gómez C, Cussó L, Guzmán‐Martínez G, Ruiz‐Cabello J, Desco M, Assoian RK, Briones AM, Andrés V. Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson-Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite. Aging Cell 2019; 18:e12936. [PMID: 30884114 PMCID: PMC6516150 DOI: 10.1111/acel.12936] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 01/23/2019] [Accepted: 02/03/2019] [Indexed: 12/11/2022] Open
Abstract
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCS Tie2Cre+/tg and LmnaLCS/LCS SM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCS SM22αCre+/tg , but not in those from LmnaLCS/LCS Tie2Cre+/tg mice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin-induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.
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Affiliation(s)
- Lara del Campo
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Amanda Sánchez‐López
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Mercedes Salaices
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto de Investigación Hospital La Paz (IdiPaz)Universidad Autónoma de MadridMadridSpain
| | - Ryan A. von Kleeck
- Center for Engineering Mechanobiology and Department of Systems Pharmacology and Translational TherapeuticsUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Elba Expósito
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Cristina González‐Gómez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
| | - Lorena Cussó
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Departamento de Bioingeniería e Ingeniería AeroespacialUniversidad Carlos III de MadridMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Spain
| | - Gabriela Guzmán‐Martínez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Cardiac Imaging Unit, Cardiology DepartmentHospital Universitario La PazMadridSpain
| | - Jesús Ruiz‐Cabello
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Respiratorias (CIBERES)Spain
- Present address:
CIC biomaGUNE and Ikerbasque Basque Foundation for ScienceSan SebastiánSpain
- Present address:
Universidad Complutense MadridMadridSpain
| | - Manuel Desco
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Departamento de Bioingeniería e Ingeniería AeroespacialUniversidad Carlos III de MadridMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Spain
| | - Richard K. Assoian
- Center for Engineering Mechanobiology and Department of Systems Pharmacology and Translational TherapeuticsUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Ana M. Briones
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto de Investigación Hospital La Paz (IdiPaz)Universidad Autónoma de MadridMadridSpain
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- CIBER de Enfermedades Cardiovasculares (CIBERCV)Spain
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24
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Chen X, Cao Y, Wang Z, Zhang D, Tang W. Bioinformatic analysis reveals novel hub genes and pathways associated with hypertensive nephropathy. Nephrology (Carlton) 2019; 24:1103-1114. [PMID: 30298691 DOI: 10.1111/nep.13508] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2018] [Indexed: 02/05/2023]
Abstract
AIM Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease and is closely associated with inflammation and tubule-interstitial fibrosis. The molecular mechanism underlying HTN remains unclear. This study used bioinformatic analysis to identify the novel gene targets for HTN. METHODS We downloaded the microarray data of GSE99325 and GSE32591 from Gene Expression Omnibus. The dataset comprised 20 HTN and 15 normal samples. The differentially expressed genes (DEG) were identified, and then gene ontology (GO) enrichment was performed, and a GO tree was constructed by using clusterProfiler and ClueGO. In addition, a protein-protein interaction network was established using the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape. The novel hub genes were validated in in vitro experiments. RESULTS A total of 267 genes (117 up-regulated and 150 down-regulated genes) were identified as DEG. GO analysis and the GO tree indicated that the DEG were mainly associated with steroid hormone response and the extracellular matrix. Based on the protein-protein interaction network, we screened out several novel hub genes. Considering the findings and the literature review, we focused on and validated the dual specificity phosphatase 1, tissue inhibitor of matrix metalloproteinases 1, fos proto-oncogene and jun proto-oncogenes, which may play significant roles in the pathogenesis of HTN. These findings were consistent with the bioinformatic results for the in vitro validation. CONCLUSION This study identified for the first time novel hub genes with microarray data in HTN by using bioinformatic analysis and provided novel evidence and clues for future works.
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Affiliation(s)
- Xiaolei Chen
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Yiling Cao
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Zheng Wang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Dongmei Zhang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Wanxin Tang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
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25
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Vousden KA, Lundqvist T, Popovic B, Naiman B, Carruthers AM, Newton P, Johnson DJD, Pomowski A, Wilkinson T, Dufner P, de Mendez I, Mallinder PR, Murray C, Strain M, Connor J, Murray LA, Sleeman MA, Lowe DC, Huntington JA, Vaughan TJ. Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1. Sci Rep 2019; 9:1605. [PMID: 30733557 PMCID: PMC6367345 DOI: 10.1038/s41598-019-38842-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 01/10/2019] [Indexed: 01/21/2023] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) that regulates fibrinolysis, cell adhesion and cell motility via its interactions with plasminogen activators and vitronectin. PAI-1 has been shown to play a role in a number of diverse pathologies including cardiovascular diseases, obesity and cancer and is therefore an attractive therapeutic target. However the multiple patho-physiological roles of PAI-1, and understanding the relative contributions of these in any one disease setting, make the development of therapeutically relevant molecules challenging. Here we describe the identification and characterisation of fully human antibody MEDI-579, which binds with high affinity and specificity to the active form of human PAI-1. MEDI-579 specifically inhibits serine protease interactions with PAI-1 while conserving vitronectin binding. Crystallographic analysis reveals that this specificity is achieved through direct binding of MEDI-579 Fab to the reactive centre loop (RCL) of PAI-1 and at the same exosite used by both tissue and urokinase plasminogen activators (tPA and uPA). We propose that MEDI-579 acts by directly competing with proteases for RCL binding and as such is able to modulate the interaction of PAI-1 with tPA and uPA in a way not previously described for a human PAI-1 inhibitor.
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Affiliation(s)
| | - Tomas Lundqvist
- AstraZeneca AB R&D, Pepparedsleden 1, 431 50, Mölndal, Sweden
| | | | - Brian Naiman
- MedImmune LLC, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | | | | | - Daniel J D Johnson
- Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Anja Pomowski
- Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | | | | | | | | | - Clare Murray
- AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK
| | | | - Jane Connor
- MedImmune LLC, One MedImmune Way, Gaithersburg, MD, 20878, USA
| | | | | | | | - James A Huntington
- Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
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26
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Kanno Y. The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis. Int J Mol Sci 2019; 20:ijms20030619. [PMID: 30709025 PMCID: PMC6387418 DOI: 10.3390/ijms20030619] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/28/2019] [Accepted: 01/29/2019] [Indexed: 02/08/2023] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc.
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Affiliation(s)
- Yosuke Kanno
- Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto 610-0395, Japan.
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27
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Pavlov M, Ćelap I. Plasminogen activator inhibitor 1 in acute coronary syndromes. Clin Chim Acta 2019; 491:52-58. [PMID: 30659821 DOI: 10.1016/j.cca.2019.01.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/14/2019] [Accepted: 01/15/2019] [Indexed: 11/24/2022]
Abstract
Plasminogen activator inhibitor 1 (PAI-1) is the main regulator of endogenous fibrinolysis, overriding the impact of other constituents of fibrinolysis. In plasma, it can be found in three forms: active, latent and inactive. There are numerous commercially available tests, analysing the activity of PAI-1 or the antigen level, with variable correlations between the two. PAI-1 has been extensively studied regarding incidence and outcomes of acute coronary syndromes, and showed positive association with both in numerous studies. Higher PAI-1 has been associated with worse short- and long-term outcomes. Studies are more consistent in the primary percutaneous coronary intervention era. Higher rise of PAI-1 within the first 24 h of acute myocardial infarction has been linked to some of its high-risk features. The circadian pattern of PAI-1 kinetics has been previously described, and the mechanisms behind this phenomenon and its impact on the incidence of acute coronary syndromes are well known. Further investigations are needed to test the safety and efficacy of PAI-1 as a pharmacological target in cardiovascular diseases.
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Affiliation(s)
- Marin Pavlov
- Department of Cardiology, Sestre milosrdnice University Hospital Centre, Vinogradska cesta 29, 10000 Zagreb, Croatia.
| | - Ivana Ćelap
- Department of Clinical Chemistry, Sestre milosrdnice University Hospital Centre, Vinogradska cesta 29, 10000 Zagreb, Croatia
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28
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Henkel AS, Khan SS, Olivares S, Miyata T, Vaughan DE. Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice. Hepatol Commun 2018; 2:1479-1492. [PMID: 30556037 PMCID: PMC6287480 DOI: 10.1002/hep4.1259] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 08/24/2018] [Indexed: 01/08/2023] Open
Abstract
Plasminogen activator inhibitor 1 (PAI‐1), an essential regulator of fibrinolysis, is increasingly implicated in the pathogenesis of metabolic disorders, such as obesity and nonalcoholic fatty liver disease (NAFLD). Pharmacologic inhibition of PAI‐1 is emerging as a highly promising therapeutic strategy for obesity and its sequelae. Given the well‐established profibrotic function of PAI‐1, we considered whether PAI‐1 may serve as a target for antifibrotic therapy in nonalcoholic steatohepatitis (NASH). We therefore determined the effect of genetic Pai‐1 deletion and pharmacologic PAI‐1 inhibition on the development of NASH‐related fibrosis in mice. Pai‐1 knockout (Pai‐1–/–) and wild‐type control (Pai‐1+/+) mice were fed a high‐fat/high‐cholesterol high‐sugar (HFHS) diet or a methionine‐ and choline‐deficient (MCD) diet to induce steatohepatitis with fibrosis. PAI‐1 was pharmacologically inhibited using the small molecule inhibitor TM5441 in wild‐type C57BL/6 mice fed an HFHS or MCD diet. Either genetic deletion of Pai‐1 or pharmacologic inhibition of PAI‐1 attenuated MCD diet‐induced hepatic steatosis but did not prevent hepatic inflammation or fibrosis. Targeted inhibition of PAI‐1 conferred transient protection from HFHS diet‐induced obesity and hepatic steatosis, an effect that was lost with prolonged exposure to the obesigenic diet. Neither genetic deletion of Pai‐1 nor pharmacologic inhibition of PAI‐1 prevented HFHS diet‐induced hepatic inflammation or fibrosis. Conclusion:Pai‐1 regulates hepatic lipid accumulation but does not promote NASH progression. The PAI‐1 inhibitor TM5441 effectively attenuates diet‐induced obesity and hepatic steatosis but does not prevent NASH‐related fibrosis in mice.
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Affiliation(s)
- Anne S Henkel
- Department of Medicine Northwestern University Chicago IL.,Jesse Brown VA Medical Center Chicago IL
| | - Sadiya S Khan
- Department of Medicine Northwestern University Chicago IL
| | | | - Toshio Miyata
- Department of Medicine Northwestern University Chicago IL
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29
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Pavlov M, Nikolić-Heitzler V, Babić Z, Milošević M, Kordić K, Ćelap I, Degoricija V. Plasminogen activator inhibitor-1 activity and long-term outcome in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: a prospective cohort study. Croat Med J 2018; 59:108-117. [PMID: 29972733 PMCID: PMC6045897 DOI: 10.3325/cmj.2018.59.108] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 05/14/2018] [Indexed: 11/05/2022] Open
Abstract
AIM To determine the relationship between plasminogen activator inhibitor-1 (PAI-1) activity rise during the first 24 hours of ST-elevation myocardial infarction (STEMI) treatment and death after 5 years. METHODS From May 1, 2009 to March 23, 2010, 87 STEMI patients treated with primary percutaneous coronary intervention (PCI) at the Sestre Milosrdnice University Hospital Center were consecutively enrolled in prospective single-center cohort study. PAI-1 activity was determined on admission and 24 hours later. The primary end-point was death after 5 years. The predictive value of PAI-1 activity variables as biomarkers of death was assessed using receiver operating characteristic (ROC) curve, independent predictors of death were assessed using multivariate Cox regression, and covariates independently related to higher PAI-1 activity rise were assessed using linear regression. RESULTS Two patients died during the hospital treatment and 11 during the follow-up. PAI-1 activity rise had the largest area under curve (0.748) for predicting death rate (optimal cut-off point 3.7 U/mL, sensitivity 53.8%, specificity 90.5%). Patients with PAI-1 activity rise higher than 3.7 U/mL had significantly higher mortality (P<0.001). Kaplan-Meier survival curve diverged within the first year after STEMI. Independent predictors of death were PAI-1 rise and final Thrombolysis in Myocardial Infarction flow. PAI-1 activity rise was independently related to heart failure, thrombus aspiration, and body weight. CONCLUSION PAI-1 activity rise higher than 3.7 U/mL is associated with higher 5-year death rate in STEMI patients treated with primary PCI.
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Affiliation(s)
- Marin Pavlov
- Marin Pavlov, Department of Cardiology, Sestre Milosrdnice University Hospital Center, Vinogradska cesta 29, 10000 Zagreb, Croatia,
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30
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Michael OS, Olatunji LA. Ameliorative effect of nicotine exposure on insulin resistance is accompanied by decreased cardiac glycogen synthase kinase-3 and plasminogen activator inhibitor-1 during oral oestrogen-progestin therapy. Arch Physiol Biochem 2018; 124:139-148. [PMID: 28868937 DOI: 10.1080/13813455.2017.1369549] [Citation(s) in RCA: 14] [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] [Indexed: 12/21/2022]
Abstract
CONTEXT Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. OBJECTIVE We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase-3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). METHODS Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 µg levonorgestrel plus 1.0 µg ethinylestradiol daily for 8 weeks. RESULTS Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. CONCLUSION Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone.
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Affiliation(s)
- Olugbenga S Michael
- a Cardiovascular Research Laboratory, Department of Physiology , University of Ilorin, Ilorin, Nigeria
- b Hope Cardiometabolic Research Centre , Ilorin , Nigeria
- c Cardiometabolic Research Unit, Department of Physiology , College of Health sciences, Bowen University , Iwo , Nigeria
| | - Lawrence A Olatunji
- a Cardiovascular Research Laboratory, Department of Physiology , University of Ilorin, Ilorin, Nigeria
- b Hope Cardiometabolic Research Centre , Ilorin , Nigeria
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Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study. J Hypertens 2018; 35:1787-1793. [PMID: 28379891 DOI: 10.1097/hjh.0000000000001375] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Deficient plasminogen activator inhibitor-1 (PAI-1) prevented hypertension in mice. Plasma PAI-1 was associated with hypertension in cross-sectional analyses, but the prospective association of PAI-1 with incident hypertension in large epidemiological studies is scarce. METHODS Leveraging two longitudinal cohorts of American Indians in the Strong Heart Study (SHS, N = 1019) and the Strong Heart Family Study (SHFS, N = 1502), we examined the prospective association of plasma PAI-1 with incident hypertension by multivariate logistic regression, adjusting for age, sex, study site, smoking, drinking, dietary sodium, obesity, lipids, fasting glucose, kidney function, inflammation, and follow-up years. Family relatedness in the SHFS was accounted for using the GLIMMIX procedure. Plasma PAI-1 level at baseline was measured by immunoassay. All participants were free of hypertension, cardiovascular diseases, and chronic kidney disease at baseline. RESULTS A total of 305 and 258 participants, respectively, from the SHS (57 ± 7 years) and the SHFS (33 ± 13 years) developed incident hypertension during follow-up. In the SHS, higher level of log-transformed PAI-1 was associated with 1.35-fold increased risk of hypertension [odds ratio (OR) (95% confidence interval): 1.35 (1.06-1.72)]. Analysis using categorical PAI-1 (in tertiles) showed that participants in the highest tertile (≥58 ng/ml) had 63% increased risk for hypertension [OR = 1.63 (1.12-2.37)] compared with those in the lowest tertile (<33 ng/ml). This association was confirmed in the SHFS with similar effect sizes [OR = 1.41 (1.11-1.81) for log-transformed PAI-1; OR = 1.64 (1.08-2.50) for categorical PAI-1: ≥58 vs. <33 ng/ml]. CONCLUSION A higher level of plasma PAI-1 is significantly associated with hypertension in American Indians, independent of established risk factors. The potential causality warrants further investigation.
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Milenkovic J, Milojkovic M, Jevtovic Stoimenov T, Djindjic B, Miljkovic E. Mechanisms of plasminogen activator inhibitor 1 action in stromal remodeling and related diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017; 161:339-347. [PMID: 29097819 DOI: 10.5507/bp.2017.046] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 10/20/2017] [Indexed: 01/11/2023] Open
Abstract
Plasminogen activator inhibitor type 1 (PAI-1) is the main physiologic inhibitor of fibrinolysis. However, it is also involved in many physiological processes such as extracellular matrix (ECM) proteolysis and remodeling, cell adhesion, motility, and apoptosis, angiogenesis, etc. The aim of the study was to summarize current knowledge and gain insights into the mechanisms of PAI-1 action in the processes of stromal remodeling and diseases with considerable matrix pathologies (atherosclerosis, tissue fibrosis, cancer metastasis, pregnancy related complications, etc). As a component of an early cellular response to injury, PAI-1 reacts with membrane surface proteins and participates in the initiation of intracellular signaling, specifically cytoskeletal reorganization and motility. Complexity of ECM homeostasis resides in varying relation of the plasminogen system components and other matrix constituents. Inflammatory mediators (transforming growth factor-β and interferon-γ) and hormones (angiotensin II) are in the close interdependent relation with PAI-1. Also, special attention is devoted to the role of increased PAI-1 concentrations due to the common 4G/5G polymorphism. Some of the novel mechanisms of ECM modification consider PAI-1 dependent stabilization of urokinase mediated cell adhesion, control of the vascular endothelial cadherin trafficking and interaction with endothelial cells proteasome, its relation to matrix metalloproteinase 2 and osteopontin, and oxidative inhibition by myeloperoxidase. Targeting and/or alteration of PAI-1 functions might bring benefit to the future therapeutic approaches in diseases where ECM undergoes substantial remodeling.
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Affiliation(s)
- Jelena Milenkovic
- Institute of Pathophysiology, Faculty of Medicine University of Nis, Serbia
| | - Maja Milojkovic
- Institute of Pathophysiology, Faculty of Medicine University of Nis, Serbia
| | | | - Boris Djindjic
- Institute of Pathophysiology, Faculty of Medicine University of Nis, Serbia
| | - Edita Miljkovic
- Hematology and Clinical Immunology Clinic, Clinical Center in Nis, Serbia
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Svenningsen P, Hinrichs GR, Zachar R, Ydegaard R, Jensen BL. Physiology and pathophysiology of the plasminogen system in the kidney. Pflugers Arch 2017; 469:1415-1423. [DOI: 10.1007/s00424-017-2014-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/09/2017] [Accepted: 06/12/2017] [Indexed: 12/31/2022]
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D'Elia JA, Bayliss G, Gleason RE, Weinrauch LA. Cardiovascular-renal complications and the possible role of plasminogen activator inhibitor: a review. Clin Kidney J 2016; 9:705-12. [PMID: 27679717 PMCID: PMC5036907 DOI: 10.1093/ckj/sfw080] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 07/20/2016] [Indexed: 12/14/2022] Open
Abstract
Since angiotensin increases the expression of plasminogen activator inhibitor (PAI), mechanisms associated with an actively functioning renin–angiotensin–aldosterone system can be expected to be associated with increased PAI-1 expression. These mechanisms are present not only in common conditions resulting in glomerulosclerosis associated with aging, diabetes or genetic mutations, but also in autoimmune disease (like scleroderma and lupus), radiation injury, cyclosporine toxicity, allograft nephropathy and ureteral obstruction. While the renin–angiotensin–aldosterone system and growth factors, such as transforming growth factor-beta (TGF-β), are almost always part of the process, there are rare experimental observations of PAI-1 expression without their interaction. Here we review the literature on PAI-1 and its role in vascular, fibrotic and oxidative injury as well as work suggesting potential areas of intervention in the pathogenesis of multiple disorders.
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Affiliation(s)
- John A D'Elia
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - George Bayliss
- Division ofKidney Diseases and Hypertension, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA; The Miriam Hospital, Providence, RI, USA; Alpert Medical School, Brown University, Providence, RI, USA
| | - Ray E Gleason
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
| | - Larry A Weinrauch
- Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; EP Joslin Research Laboratory, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA
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Gopal K, Gowtham M, Sachin S, Ravishankar Ram M, Shankar EM, Kamarul T. Attrition of Hepatic Damage Inflicted by Angiotensin II with α-Tocopherol and β-Carotene in Experimental Apolipoprotein E Knock-out Mice. Sci Rep 2015; 5:18300. [PMID: 26670291 PMCID: PMC4680930 DOI: 10.1038/srep18300] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 11/12/2015] [Indexed: 12/15/2022] Open
Abstract
Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology.
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Affiliation(s)
- Kaliappan Gopal
- Center for Cellular and Molecular Biology (CCMB), Uppal Road, 500007, Hyderabad, India
- Department of Orthopedic Surgery, Tissue Engineering Group (TEG), National Orthopedics Center for Excellence in Research and Learning (NOCERAL), Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia
| | - Munusamy Gowtham
- Center for Cellular and Molecular Biology (CCMB), Uppal Road, 500007, Hyderabad, India
| | - Singh Sachin
- Center for Cellular and Molecular Biology (CCMB), Uppal Road, 500007, Hyderabad, India
| | - Mani Ravishankar Ram
- Department of Bio-Medical Science, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia
| | - Esaki M. Shankar
- Tropical Infectious Disease Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia
| | - Tunku Kamarul
- Department of Orthopedic Surgery, Tissue Engineering Group (TEG), National Orthopedics Center for Excellence in Research and Learning (NOCERAL), Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia
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Boe AE, Eren M, Morales-Nebreda L, Murphy SB, Budinger GRS, Mutlu GM, Miyata T, Vaughan DE. Nitric oxide prevents alveolar senescence and emphysema in a mouse model. PLoS One 2015; 10:e0116504. [PMID: 25756287 PMCID: PMC4355068 DOI: 10.1371/journal.pone.0116504] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 12/01/2014] [Indexed: 12/23/2022] Open
Abstract
Nω-nitro-L-arginine methyl ester (L-NAME) treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO) production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction) and functional (increased compliance and reduced elastance) characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1). Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging.
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Affiliation(s)
- Amanda E. Boe
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Mesut Eren
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Luisa Morales-Nebreda
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Sheila B. Murphy
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - G. R. Scott Budinger
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Gökhan M. Mutlu
- Pulmonary and Critical Care Section, Department of Medicine, University of Chicago, Chicago, IL, United States of America
| | - Toshio Miyata
- United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Douglas E. Vaughan
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
- * E-mail:
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Agirbasli M, Eren M, Yasar S, Delil K, Goktay F, Oner ET, Vaughan DE. Functionally stable plasminogen activator inhibitor-1 in a family with cardiovascular disease and vitiligo. J Thromb Thrombolysis 2015; 38:50-6. [PMID: 24197654 DOI: 10.1007/s11239-013-1021-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Vitiligo is a common skin condition with a complex pathophysiology characterized by the lack of pigmentation due to melanocyte degeneration. In this study, we investigated PAI-1 antigen (Ag) and activity levels in a 34 year old male with extensive vascular disease, alopecia areata and vitiligo. Fasting PAI-1 Ag and activity levels were measured at 9 a.m. in the subject and family members. Both PAI-1 Ag (67 ± 38 vs. 18.6 ± 6.5 ng/ml, P < 0.001) and specific activity (15.8 ± 10.0 vs. 7.6 ± 6.0 IU/pmol, P < 0.04) levels of PAI-1 were moderately elevated in subjects compared to the controls. PAI-1 kinetic studies demonstrated a markedly enhanced stability of plasma PAI-1 activity in the family members. Specific activity at 16 h was significantly higher than expected activity levels (0.078 ± 0.072 vs. 0.001 ± 0.001 IU/ng/ml, P < 0.001). While the exact mechanism of increased stability of PAI-1 activity in vitiligo is not known, it is likely due to post-translational modifications or increased binding affinity for a stabilizing cofactor. In conclusion, enhanced stability of PAI-1 may contribute to the pathophysiology of vascular disease and associated melanocyte degeneration. Systemic or local treatment with PAI-1 inhibitors may offer a potential treatment alternative to the near orphan status for vitiligo drug development.
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Affiliation(s)
- Mehmet Agirbasli
- Department of Cardiology, Faculty of Medicine, Marmara University Hospital, Yeşilbahar Sok 68/14 Palmiye Apt., Goztepe Kadikoy, 34726, Istanbul, Turkey,
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Marudamuthu AS, Shetty SK, Bhandary YP, Karandashova S, Thompson M, Sathish V, Florova G, Hogan TB, Pabelick CM, Prakash YS, Tsukasaki Y, Fu J, Ikebe M, Idell S, Shetty S. Plasminogen activator inhibitor-1 suppresses profibrotic responses in fibroblasts from fibrotic lungs. J Biol Chem 2015; 290:9428-41. [PMID: 25648892 DOI: 10.1074/jbc.m114.601815] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Indexed: 02/04/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive interstitial scarification. A hallmark morphological lesion is the accumulation of myofibroblasts or fibrotic lung fibroblasts (FL-fibroblasts) in areas called fibroblastic foci. We previously demonstrated that the expression of both urokinase-type plasminogen activator (uPA) and the uPA receptor are elevated in FL-fibroblasts from the lungs of patients with IPF. FL-fibroblasts isolated from human IPF lungs and from mice with bleomycin-induced pulmonary fibrosis showed an increased rate of proliferation compared with normal lung fibroblasts (NL-fibroblasts) derived from histologically "normal" lung. Basal expression of plasminogen activator inhibitor-1 (PAI-1) in human and murine FL-fibroblasts was reduced, whereas collagen-I and α-smooth muscle actin were markedly elevated. Conversely, alveolar type II epithelial cells surrounding the fibrotic foci in situ, as well as those isolated from IPF lungs, showed increased activation of caspase-3 and PAI-1 with a parallel reduction in uPA expression. Transduction of an adenovirus PAI-1 cDNA construct (Ad-PAI-1) suppressed expression of uPA and collagen-I and attenuated proliferation in FL-fibroblasts. On the contrary, inhibition of basal PAI-1 in NL-fibroblasts increased collagen-I and α-smooth muscle actin. Fibroblasts isolated from PAI-1-deficient mice without lung injury also showed increased collagen-I and uPA. These changes were associated with increased Akt/phosphatase and tensin homolog proliferation/survival signals in FL-fibroblasts, which were reversed by transduction with Ad-PAI-1. This study defines a new role of PAI-1 in the control of fibroblast activation and expansion and its role in the pathogenesis of fibrosing lung disease and, in particular, IPF.
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Affiliation(s)
- Amarnath S Marudamuthu
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Shwetha K Shetty
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Yashodhar P Bhandary
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Sophia Karandashova
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Michael Thompson
- the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and
| | | | - Galina Florova
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Taryn B Hogan
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | | | - Y S Prakash
- the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, and
| | - Yoshikazu Tsukasaki
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Jian Fu
- the Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536
| | - Mitsuo Ikebe
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Steven Idell
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708
| | - Sreerama Shetty
- From the Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas 75708,
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Huang WT, Akhter H, Jiang C, MacEwen M, Ding Q, Antony V, Thannickal VJ, Liu RM. Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis. Exp Gerontol 2014; 61:62-75. [PMID: 25451236 DOI: 10.1016/j.exger.2014.11.018] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 11/24/2014] [Accepted: 11/27/2014] [Indexed: 12/31/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.
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Affiliation(s)
- Wen-Tan Huang
- Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA
| | - Hasina Akhter
- Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA
| | - Chunsun Jiang
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Mark MacEwen
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, USA
| | - Qiang Ding
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Veena Antony
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Victor John Thannickal
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA
| | - Rui-Ming Liu
- Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, USA.
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Li ZQ, Liu YL, Li G, Li B, Liu Y, Li XF, Liu AJ. Inhibitory effects of C-type natriuretic peptide on the differentiation of cardiac fibroblasts, and secretion of monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1. Mol Med Rep 2014; 11:159-65. [PMID: 25352084 PMCID: PMC4237089 DOI: 10.3892/mmr.2014.2763] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 05/28/2014] [Indexed: 01/03/2023] Open
Abstract
The present study aimed to investigate the effect of C-type natriuretic peptide (CNP) on the function of cardiac fibroblasts (CFs). Western blotting was used to investigate the expression of myofibroblast marker proteins: α-smooth muscle actin (α-SMA), extra domain-A fibronectin, collagen I and collagen III, and the activity of extracellular signal-regulated kinase 1/2 (ERK1/2). Immunofluorescence was used to examine the morphological changes; a transwell assay was used to analyze migration, and reverse transcription-quantitative polymerase chain reaction and ELISA were employed to determine the mRNA expression and protein secretion of monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1). The results demonstrated that CNP significantly reduced the protein expression of α-SMA, fibronectin, collagen I and collagen III, and suppressed the migratory ability of CFs. Additionally, the mRNA and protein expression of MCP-1 and PAI-1 was inhibited under the CNP treatment; and this effect was mediated by the inhibition of the ERK1/2 activity. In conclusion, CNP inhibited cardiac fibroblast differentiation and migration, and reduced the secretion of MCP-1 and PAI-1, which demonstrates novel mechanisms to explain the antifibrotic effect of CNP.
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Affiliation(s)
- Zhi-Qiang Li
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Ying-Long Liu
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Gang Li
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Bin Li
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Yang Liu
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Xiao-Feng Li
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Ai-Jun Liu
- Department of Pediatric Cardiac Surgery Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
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Functional stability of plasminogen activator inhibitor-1. ScientificWorldJournal 2014; 2014:858293. [PMID: 25386620 PMCID: PMC4214104 DOI: 10.1155/2014/858293] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 09/17/2014] [Indexed: 12/23/2022] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT) and myocardial infarction (MI). The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.
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Wan Y, Gao P, Zhou S, Zhang Z, Hao D, Lian L, Li Y, Chen H, Liu D. SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence. Aging Cell 2014; 13:890-9. [PMID: 25040736 PMCID: PMC4331759 DOI: 10.1111/acel.12247] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2014] [Indexed: 12/20/2022] Open
Abstract
The inactivation of plasminogen activator inhibitor-1 (PAI-1) has been shown to exert beneficial effects in age-related vascular diseases. Limited information is available on the molecular mechanisms regarding the negatively regulated expression of PAI-1 in the vascular system. In this study, we observed an inverse correlation between SIRT1, a class III histone deacetylase, and PAI-1 expression in human atherosclerotic plaques and the aortas of old mice, suggesting that internal negative regulation exists between SIRT1 and PAI-1. SIRT1 overexpression reversed the increased PAI-1 expression in senescent human umbilical vein endothelial cells (HUVECs) and aortas of old mice, accompanied by decreased SA-β-gal activity in vitro and improved endothelial function and reduced arterial stiffness in vivo. Moreover, the SIRT1-mediated inhibition of PAI-1 expression exerted an antisenescence effect in HUVECs. Furthermore, we demonstrated that SIRT1 is able to bind to the PAI-1 promoter, resulting in a decrease in the acetylation of histone H4 lysine 16 (H4K16) on the PAI-1 promoter region. Thus, our findings suggest that the SIRT1-mediated epigenetic inhibition of PAI-1 expression exerts a protective effect in vascular endothelial senescence.
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Affiliation(s)
- Yan‐Zhen Wan
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - Peng Gao
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - Shuang Zhou
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - Zhu‐Qin Zhang
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - De‐Long Hao
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - Li‐Shan Lian
- Department of Vascular Surgery Peking Union Medical College Hospital Peking Union Medical College Chinese Academy of Medical Science Beijing 100730 China
| | - Yong‐Jun Li
- Department of Vascular Surgery Peking Union Medical College Hospital Peking Union Medical College Chinese Academy of Medical Science Beijing 100730 China
| | - Hou‐Zao Chen
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - De‐Pei Liu
- State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
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Eren M, Boe AE, Klyachko EA, Vaughan DE. Role of plasminogen activator inhibitor-1 in senescence and aging. Semin Thromb Hemost 2014; 40:645-51. [PMID: 25173500 DOI: 10.1055/s-0034-1387883] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The average age of the US population continues to increase. Age is the most important determinant of disease and disability in humans, but the fundamental mechanisms of aging remain largely unknown. Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging. While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in kl/kl and N(ω)-nitro-l-arginine methyl ester-treated wild-type mice. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies.
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Affiliation(s)
- Mesut Eren
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Amanda E Boe
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Ekaterina A Klyachko
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Douglas E Vaughan
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Giani JF, Janjulia T, Kamat N, Seth DM, Blackwell WLB, Shah KH, Shen XZ, Fuchs S, Delpire E, Toblli JE, Bernstein KE, McDonough AA, Gonzalez-Villalobos RA. Renal angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition. J Am Soc Nephrol 2014; 25:2752-63. [PMID: 25012170 DOI: 10.1681/asn.2013091030] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.
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Affiliation(s)
- Jorge F Giani
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Tea Janjulia
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nikhil Kamat
- Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Dale M Seth
- Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana
| | - Wendell-Lamar B Blackwell
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kandarp H Shah
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Xiao Z Shen
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Sebastien Fuchs
- Department of Basic Medical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California
| | - Eric Delpire
- Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee; and
| | - Jorge E Toblli
- Laboratory of Experimental Medicine, Alemán Hospital, Buenos Aires, Argentina
| | - Kenneth E Bernstein
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Alicia A McDonough
- Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Romer A Gonzalez-Villalobos
- Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California;
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Relationship of coagulation and fibrinolytic variables with arterial structure and function in Africans. Thromb Res 2014; 134:78-83. [PMID: 24824291 DOI: 10.1016/j.thromres.2014.04.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 04/11/2014] [Accepted: 04/21/2014] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Although both coagulation and fibrinolysis are associated with cardiovascular disease (CVD) the underlying nature and pathways of many of these associations are still unclear. Our aim was to determine which of the current or 5-year prior levels of total fibrinogen, fibrinogen γ', plasminogen activator inhibitor-1 (PAI-1act) and global fibrinolytic potential were the stronger determinant of arterial structure and function. MATERIALS AND METHODS This prospective study consisted of 2010 Africans over the age of 35 years with 5-year follow-up data available for 1288 participants. Cardiovascular measurements included arterial stiffness, blood pressure and carotid intima media thickness. RESULTS Fibrinogen γ' showed stronger associations with blood pressure than total fibrinogen also in the presence of other CVD risk factors. PAI-1act was positively associated with blood pressure both cross-sectionally and prospectively, with the longitudinal association being the stronger determinant, also after adjustment for known CVD risk factors. Clot lysis time (CLT) was positively associated, both prospectively and cross-sectionally, with intima media thickness and negatively with markers of arterial stiffness but not after adjustment for known CVD risk factors. CONCLUSIONS Fibrinogen γ' was more strongly associated with CVD function than total fibrinogen. PAI-1act was significantly associated with blood pressure with changes in PAI-1 levels preceding changes in blood pressure. Different mechanisms may be at play determining arterial wall stiffness/thickening and blood pressure as observed from the opposing associations with PAI-1act and CLT. CLT was not independently related to cardiovascular measures as its associations were weakened in the presence of other known CVD risk factors.
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Zhang X, Thatcher S, Wu C, Daugherty A, Cassis LA. Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms. J Vasc Surg 2014; 61:767-76. [PMID: 24439319 DOI: 10.1016/j.jvs.2013.11.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 10/31/2013] [Accepted: 11/01/2013] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Male sex is a nonmodifiable risk factor for abdominal aortic aneurysm (AAA) development. Similar to humans, male mice are more susceptible to angiotensin II (AngII)-induced AAAs than female mice. Previous studies demonstrated that castration of males markedly reduced the formation of AngII-induced AAAs. Progression of AAA size is associated with increased risk of aneurysm rupture. In this study, we hypothesized that castration of male mice would reduce the progression of established AngII-induced AAAs. METHODS Male apolipoprotein E-deficient mice were infused with AngII for 1 month to induce AAA formation. Aortic diameters were measured by ultrasound imaging, and mice were stratified into two groups that underwent a sham operation or castration. AngII infusions were continued for a further 2 months. Ultrasound imaging was used to quantify lumen diameters, and excised aortas were processed for quantification of AAA size, volume, and tissue characteristics. RESULTS Sham-operated mice exhibited progressive dilation of suprarenal aortic lumen diameters during the continued AngII infusion. Aortic lumen diameters were significantly decreased in castrated mice (n = 17) compared with sham-operated mice (n = 15) at study end point (1.63 ± 0.04 vs 1.88 ± 0.05 mm; P < .05). However, maximal external AAA diameters were not significantly different between sham-operated and castrated mice. The vascular volume/lumen volume ratio of excised AAAs imaged by ultrasound was significantly increased by castration (9.5% ± 2.0%) vs sham operation (4.8% ± 0.9%; n = 11 per group; P < .05). Moreover, compared with the thin-walled AAAs of sham-operated mice, aneurysm sections from castrated mice exhibited increased smooth muscle α-actin and collagen. CONCLUSIONS Removal of endogenous male hormones by castration selectively reduces aortic lumen expansion while not altering the external AAA dimensions. CLINICAL RELEVANCE There are no therapeutics that slow the progression of abdominal aortic aneurysms (AAAs), and as the size of an AAA increases, so does the risk of rupture and death. Male sex is a nonmodifiable risk factor for AAA development, but whether male sex hormones have a similar effect on AAA progression is unclear. Removal of male sex hormones in an established mouse model of angiotensin II-induced AAAs resulted in reduced progressive lumen dilation while not altering external AAA dimensions. Therapies that limit androgen action may provide benefit against AAA progression. Alternatively, supplemental testosterone may be contraindicated in men diagnosed with an AAA.
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Affiliation(s)
- Xuan Zhang
- Graduate Center for Toxicology, University of Kentucky, Lexington, Ky
| | - Sean Thatcher
- Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Ky
| | - Congqing Wu
- Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Ky
| | - Alan Daugherty
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, Ky
| | - Lisa A Cassis
- Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Ky.
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Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A, Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE. Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation 2013; 128:2318-24. [PMID: 24092817 DOI: 10.1161/circulationaha.113.003192] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Long-term inhibition of nitric oxide synthase by L-arginine analogues such as N(ω)-nitro-l-arginine methyl ester (L-NAME) has been shown to induce senescence in vitro and systemic hypertension and arteriosclerosis in vivo. We previously reported that plasminogen activator inhibitor-1 (PAI-1)-deficient mice (PAI-1(-/-)) are protected against L-NAME-induced pathologies. In this study, we investigated whether a novel, orally active PAI-1 antagonist (TM5441) has a similar protective effect against L-NAME treatment. Additionally, we studied whether L-NAME can induce vascular senescence in vivo and investigated the role of PAI-1 in this process. METHODS AND RESULTS Wild-type mice received either L-NAME or L-NAME and TM5441 for 8 weeks. Systolic blood pressure was measured every 2 weeks. We found that TM5441 attenuated the development of hypertension and cardiac hypertrophy compared with animals that had received L-NAME alone. Additionally, TM5441-treated mice had a 34% reduction in periaortic fibrosis relative to animals on L-NAME alone. Finally, we investigated the development of vascular senescence by measuring p16(Ink4a) expression and telomere length in aortic tissue. We found that L-NAME increased p16(Ink4a) expression levels and decreased telomere length, both of which were prevented with TM5441 cotreatment. CONCLUSIONS Pharmacological inhibition of PAI-1 is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis in mice treated with L-NAME. Furthermore, PAI-1 inhibition attenuates the arterial expression of p16(Ink4a) and maintains telomere length. PAI-1 appears to play a pivotal role in vascular senescence, and these findings suggest that PAI-1 antagonists may provide a novel approach in preventing vascular aging and hypertension.
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Affiliation(s)
- Amanda E Boe
- Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D.M., L.H.S.), Sanford Burnham Medical Research Institute at Lake Nona, Orlando FL
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Beier JI, Arteel GE. Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism. Exp Biol Med (Maywood) 2012; 237:1-9. [PMID: 22238286 DOI: 10.1258/ebm.2011.011255] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.
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Affiliation(s)
- Juliane I Beier
- Department of Pharmacology and Toxicology and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
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Kvietys PR, Granger DN. Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radic Biol Med 2012; 52:556-592. [PMID: 22154653 PMCID: PMC3348846 DOI: 10.1016/j.freeradbiomed.2011.11.002] [Citation(s) in RCA: 223] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Revised: 11/04/2011] [Accepted: 11/04/2011] [Indexed: 12/23/2022]
Abstract
Inflammation is a complex and potentially life-threatening condition that involves the participation of a variety of chemical mediators, signaling pathways, and cell types. The microcirculation, which is critical for the initiation and perpetuation of an inflammatory response, exhibits several characteristic functional and structural changes in response to inflammation. These include vasomotor dysfunction (impaired vessel dilation and constriction), the adhesion and transendothelial migration of leukocytes, endothelial barrier dysfunction (increased vascular permeability), blood vessel proliferation (angiogenesis), and enhanced thrombus formation. These diverse responses of the microvasculature largely reflect the endothelial cell dysfunction that accompanies inflammation and the central role of these cells in modulating processes as varied as blood flow regulation, angiogenesis, and thrombogenesis. The importance of endothelial cells in inflammation-induced vascular dysfunction is also predicated on the ability of these cells to produce and respond to reactive oxygen and nitrogen species. Inflammation seems to upset the balance between nitric oxide and superoxide within (and surrounding) endothelial cells, which is necessary for normal vessel function. This review is focused on defining the molecular targets in the vessel wall that interact with reactive oxygen species and nitric oxide to produce the characteristic functional and structural changes that occur in response to inflammation. This analysis of the literature is consistent with the view that reactive oxygen and nitrogen species contribute significantly to the diverse vascular responses in inflammation and supports efforts that are directed at targeting these highly reactive species to maintain normal vascular health in pathological conditions that are associated with acute or chronic inflammation.
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Affiliation(s)
- Peter R Kvietys
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - D Neil Granger
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
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Abstract
Fibrosis is defined as a fibroproliferative or abnormal fibroblast activation-related disease. Deregulation of wound healing leads to hyperactivation of fibroblasts and excessive accumulation of extracellular matrix (ECM) proteins in the wound area, the pathological manifestation of fibrosis. The accumulation of excessive levels of collagen in the ECM depends on two factors: an increased rate of collagen synthesis and or decreased rate of collagen degradation by cellular proteolytic activities. The urokinase/tissue type plasminogen activator (uPA/tPA) and plasmin play significant roles in the cellular proteolytic degradation of ECM proteins and the maintenance of tissue homeostasis. The activities of uPA/tPA/plasmin and plasmin-dependent MMPs rely mostly on the activity of a potent inhibitor of uPA/tPA, plasminogen activator inhibitor-1 (PAI-1). Under normal physiologic conditions, PAI-1 controls the activities of uPA/tPA/plasmin/MMP proteolytic activities and thus maintains the tissue homeostasis. During wound healing, elevated levels of PAI-1 inhibit uPA/tPA/plasmin and plasmin-dependent MMP activities, and, thus, help expedite wound healing. In contrast to this scenario, under pathologic conditions, excessive PAI-1 contributes to excessive accumulation of collagen and other ECM protein in the wound area, and thus preserves scarring. While the level of PAI-1 is significantly elevated in fibrotic tissues, lack of PAI-1 protects different organs from fibrosis in response to injury-related profibrotic signals. Thus, PAI-1 is implicated in the pathology of fibrosis in different organs including the heart, lung, kidney, liver, and skin. Paradoxically, PAI-1 deficiency promotes spontaneous cardiac-selective fibrosis. In this review, we discuss the significance of PAI-1 in the pathogenesis of fibrosis in multiple organs.
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Affiliation(s)
- Asish K Ghosh
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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