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Nie Y, Song C, Huang H, Mao S, Ding K, Tang H. Chromatin modifiers in human disease: from functional roles to regulatory mechanisms. MOLECULAR BIOMEDICINE 2024; 5:12. [PMID: 38584203 PMCID: PMC10999406 DOI: 10.1186/s43556-024-00175-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/21/2024] [Indexed: 04/09/2024] Open
Abstract
The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.
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Affiliation(s)
- Yali Nie
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China
| | - Chao Song
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hong Huang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Shuqing Mao
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China
| | - Kai Ding
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China
| | - Huifang Tang
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China.
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
- The First Affiliated Hospital, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
- Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, 421001, China.
- The First Affiliated Hospital, Cardiovascular Lab of Big Data and Imaging Artificial Intelligence, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Stakišaitis D, Kapočius L, Valančiūtė A, Balnytė I, Tamošuitis T, Vaitkevičius A, Sužiedėlis K, Urbonienė D, Tatarūnas V, Kilimaitė E, Gečys D, Lesauskaitė V. SARS-CoV-2 Infection, Sex-Related Differences, and a Possible Personalized Treatment Approach with Valproic Acid: A Review. Biomedicines 2022; 10:biomedicines10050962. [PMID: 35625699 PMCID: PMC9138665 DOI: 10.3390/biomedicines10050962] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 02/06/2023] Open
Abstract
Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.
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Affiliation(s)
- Donatas Stakišaitis
- Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania;
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (A.V.); (I.B.); (E.K.)
- Correspondence: (D.S.); (V.L.)
| | - Linas Kapočius
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (A.V.); (I.B.); (E.K.)
| | - Angelija Valančiūtė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (A.V.); (I.B.); (E.K.)
| | - Ingrida Balnytė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (A.V.); (I.B.); (E.K.)
| | - Tomas Tamošuitis
- Department of Intensive Care Medicine, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania;
| | - Arūnas Vaitkevičius
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University Hospital Santaros Klinikos, Vilnius University, 08661 Vilnius, Lithuania;
| | - Kęstutis Sužiedėlis
- Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania;
| | - Daiva Urbonienė
- Department of Laboratory Medicine, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 2, 50161 Kaunas, Lithuania;
| | - Vacis Tatarūnas
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania; (V.T.); (D.G.)
| | - Evelina Kilimaitė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (L.K.); (A.V.); (I.B.); (E.K.)
| | - Dovydas Gečys
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania; (V.T.); (D.G.)
| | - Vaiva Lesauskaitė
- Institute of Cardiology, Laboratory of Molecular Cardiology, Lithuanian University of Health Sciences, Sukileliu Ave., 50161 Kaunas, Lithuania; (V.T.); (D.G.)
- Correspondence: (D.S.); (V.L.)
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Zúñiga-Muñoz A, García-Niño WR, Carbó R, Navarrete-López LÁ, Buelna-Chontal M. The regulation of protein acetylation influences the redox homeostasis to protect the heart. Life Sci 2021; 277:119599. [PMID: 33989666 DOI: 10.1016/j.lfs.2021.119599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/26/2021] [Accepted: 05/05/2021] [Indexed: 12/21/2022]
Abstract
The cellular damage caused by redox imbalance is involved in the pathogenesis of many cardiovascular diseases. Besides, redox imbalance is related to the alteration of protein acetylation processes, causing not only chromatin remodeling but also disturbances in so many processes where protein acetylation is involved, such as metabolism and signal transduction. The modulation of acetylases and deacetylases enzymes aids in maintaining the redox homeostasis, avoiding the deleterious cellular effects associated with the dysregulation of protein acetylation. Of note, regulation of protein acetylation has shown protective effects to ameliorate cardiovascular diseases. For instance, HDAC inhibition has been related to inducing cardiac protective effects and it is an interesting approach to the management of cardiovascular diseases. On the other hand, the upregulation of SIRT protein activity has also been implicated in the relief of cardiovascular diseases. This review focuses on the major protein acetylation modulators described, involving pharmacological and bioactive compounds targeting deacetylase and acetylase enzymes contributing to heart protection through redox homeostasis.
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Affiliation(s)
- Alejandra Zúñiga-Muñoz
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, Ignacio Chávez, 14080 Mexico City, Mexico
| | - Wylly-Ramsés García-Niño
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, Ignacio Chávez, 14080 Mexico City, Mexico
| | - Roxana Carbó
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, Ignacio Chávez, 14080 Mexico City, Mexico
| | - Luis-Ángel Navarrete-López
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, Ignacio Chávez, 14080 Mexico City, Mexico
| | - Mabel Buelna-Chontal
- Department of Cardiovascular Biomedicine, National Institute of Cardiology, Ignacio Chávez, 14080 Mexico City, Mexico.
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Konhilas JP, Sanchez JN, Regan JA, Constantopoulos E, Lopez-Pier M, Cannon DK, Skaria R, McKee LA, Chen H, Lipovka Y, Pollow D, Brooks HL. Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease. Am J Physiol Heart Circ Physiol 2020; 318:H1461-H1473. [PMID: 32383991 PMCID: PMC7311698 DOI: 10.1152/ajpheart.00555.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There is a sharp rise in cardiovascular disease (CVD) risk and progression with the onset of menopause. The 4-vinylcyclohexene diepoxide (VCD) model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. We hypothesized that menopausal female mice were more susceptible to CVD than pre- or perimenopausal females. Female mice were treated with VCD or vehicle for 20 consecutive days. Premenopausal, perimenopausal, and menopausal mice were administered angiotensin II (ANG II) or subjected to ischemia-reperfusion (I/R). Menopausal females were more susceptible to pathological ANG II-induced cardiac remodeling and cardiac injury from a myocardial infarction (MI), while perimenopausal, like premenopausal, females remained protected. Specifically, ANG II significantly elevated diastolic (130.9 ± 6.0 vs. 114.7 ± 6.2 mmHg) and systolic (156.9 ± 4.8 vs. 141.7 ± 5.0 mmHg) blood pressure and normalized cardiac mass (15.9 ± 1.0 vs. 7.7 ± 1.5%) to a greater extent in menopausal females compared with controls, whereas perimenopausal females demonstrated a similar elevation of diastolic (93.7 ± 2.9 vs. 100.5 ± 4.1 mmHg) and systolic (155.9 ± 7.3 vs. 152.3 ± 6.5 mmHg) blood pressure and normalized cardiac mass (8.3 ± 2.1 vs. 7.5 ± 1.4%) compared with controls. Similarly, menopausal females demonstrated a threefold increase in fibrosis measured by Picrosirus red staining. Finally, hearts of menopausal females (41 ± 5%) showed larger infarct sizes following I/R injury than perimenopausal (18.0 ± 5.6%) and premenopausal (16.2 ± 3.3, 20.1 ± 4.8%) groups. Using the VCD model of menopause, we provide evidence that menopausal females were more susceptible to pathological cardiac remodeling. We suggest that the VCD model of menopause may be critical to better elucidate cellular and molecular mechanisms underlying the transition to CVD susceptibility in menopausal women.NEW & NOTEWORTHY Before menopause, women are protected against cardiovascular disease (CVD) compared with age-matched men; this protection is gradually lost after menopause. We present the first evidence that demonstrates menopausal females are more susceptible to pathological cardiac remodeling while perimenopausal and cycling females are not. The VCD model permits appropriate examination of how increased susceptibility to the pathological process of cardiac remodeling accelerates from pre- to perimenopause to menopause.
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Affiliation(s)
- John P Konhilas
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Jessica N Sanchez
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Jessica A Regan
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Eleni Constantopoulos
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Marissa Lopez-Pier
- Department of Biomedical Engineering, University of Arizona, Tucson, Arizona
| | | | - Rinku Skaria
- Department of Physiology, University of Arizona, Tucson, Arizona
| | - Laurel A McKee
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Hao Chen
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Yulia Lipovka
- Department of Physiology, University of Arizona, Tucson, Arizona.,Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, Arizona
| | - Dennis Pollow
- Department of Physiology, University of Arizona, Tucson, Arizona
| | - Heddwen L Brooks
- Department of Physiology, University of Arizona, Tucson, Arizona
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5
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Arise KK, Kumar P, Garg R, Samivel R, Zhao H, Pandya K, Nguyen C, Lindsey S, Pandey KN. Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs. Sci Rep 2020; 10:4337. [PMID: 32152395 PMCID: PMC7062852 DOI: 10.1038/s41598-020-61041-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 02/20/2020] [Indexed: 01/10/2023] Open
Abstract
The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. ANP acting through natriuretic peptide receptor-A (NPRA) lowers blood pressure and blood volume. We tested hypothesis that ANG II plays critical roles in the transcriptional repression of Npr1 (encoding NPRA) and receptor function. ANG II significantly decreased NPRA mRNA and protein levels and cGMP accumulation in cultured mesangial cells and attenuated ANP-mediated relaxation of aortic rings ex vivo. The transcription factors, cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) facilitated the ANG II-mediated repressive effects on Npr1 transcription. Tyrosine kinase (TK) inhibitor, genistein and phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin reversed the ANG II-dependent repression of Npr1 transcription and receptor function. ANG II enhanced the activities of Class I histone deacetylases (HDACs 1/2), thereby decreased histone acetylation of H3K9/14ac and H4K8ac. The repressive effect of ANG II on Npr1 transcription and receptor signaling seems to be transduced by TK and PI-3K pathways and modulated by CREB, HSF-4a, HDACs, and modified histones. The current findings suggest that ANG II-mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for treatment and prevention of hypertension and cardiovascular diseases.
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Affiliation(s)
- Kiran K Arise
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Prerna Kumar
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Renu Garg
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Ramachandran Samivel
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Hanqing Zhao
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Krishna Pandya
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Christian Nguyen
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Sarah Lindsey
- Department of Pharmacology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA
| | - Kailash N Pandey
- Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, 70112, USA.
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Akhondzadeh F, Astani A, Najjari R, Samadi M, Rezvani ME, Zare F, Ranjbar AM, Safari F. Resveratrol suppresses interleukin-6 expression through activation of sirtuin 1 in hypertrophied H9c2 cardiomyoblasts. J Cell Physiol 2020; 235:6969-6977. [PMID: 32026477 DOI: 10.1002/jcp.29592] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 01/13/2020] [Indexed: 01/07/2023]
Abstract
Inflammatory cytokine, interleukin-6 (IL-6), plays an important role in the pathogenesis of cardiac hypertrophy. Recent studies have documented that resveratrol exhibits cardioprotective effects. The present study attempts to explore whether resveratrol suppreses IL-6 in hypertrophied H9c2 cardiomyoblasts through histone deacetylase, sirtuin 1 (SIRT1). To induce hypertrophy, the cells were incubated with angiotensin II (Ang II). Treatment groups were treated with different doses (1, 10, 25, 50, 75, and 100 μM) of resveratrol (R). Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell size was determined using crystal violet staining. Gene expression was assessed by real-time polymerase chain reaction technique. Enzyme-linked immunosorbent assay was used to measure IL-6 concentration. The results showed that cell area and ANP messenger RNA (mRNA) levels decreased significantly in R25+Ang, R50+Ang, and R100+Ang groups, as compared with Ang group. Therefore, 10, 20, 30, 40, and 50 μM of resveratrol were used to to evaluate its anti-inflammatory effects. The results revealed that Ang II upregulated IL-6 at both mRNA and protein levels (p < .001 vs. normal) and resveratrol (50 μM) decreased IL-6 mRNA (p < .01) and protein (p < .05) significantly in comparison to Ang group. However, in groups in which the cells were pretreated with SIRT1 inhibitor, EX-527, the response of resveratrol was partially reversed. Transcription levels of IL-6 receptor components (gp130 and gp80) did not change significantly among the experimental groups. The current data suggests that resveratrol protects H9c2 cells against Ang II-induced hypertrophy by suppression of IL-6 through SIRT1 activation.
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Affiliation(s)
- Fariba Akhondzadeh
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Akram Astani
- Department of Microbiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Razieh Najjari
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Morteza Samadi
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Ebrahim Rezvani
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Zare
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Mohammad Ranjbar
- Department of Pharmacognosy, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Safari
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Ma Y, Hu Y, Wu J, Wen J, Li S, Zhang L, Zhang J, Li Y, Li J. Epigallocatechin-3-gallate inhibits angiotensin II-induced cardiomyocyte hypertrophy via regulating Hippo signaling pathway in H9c2 rat cardiomyocytes. Acta Biochim Biophys Sin (Shanghai) 2019; 51:422-430. [PMID: 30877756 DOI: 10.1093/abbs/gmz018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/29/2019] [Accepted: 02/01/2019] [Indexed: 12/20/2022] Open
Abstract
Angiotensin II (AII) has been well known to induce cardiomyocyte hypertrophy. Epigallocatechin-3-gallate (EGCG) is the main active component of green tea and it has been shown to exhibit strong cardioprotective potential, although the underlying molecular mechanisms remain unclear. In this study, we investigated the role and mechanism of EGCG in preventing AII-induced cardiomyocyte hypertrophy using rat H9c2 cardiomyocytes cells. Reactive oxygen species assay, cell size, and mRNA expression of cardiac hypertrophy markers ANP and BNP were assessed in response to AII treatment. In addition, expression of proteins involved in Hippo signaling pathway were determined by western blot analysis. We found that AII treatment resulted in significant upregulation of ANP and BNP expression levels and increase in H9c2 cell size, which were markedly attenuated by EGCG treatment. Furthermore, our results suggested that EGCG inhibited AII-induced cardiac hypertrophy via regulating the Hippo signaling pathway. Therefore, EGCG may be an effective agent for preventing cardiac hypertrophy.
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Affiliation(s)
- Yuan Ma
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Yongjia Hu
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Jiawen Wu
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Junru Wen
- School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Sen Li
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Lijuan Zhang
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Jie Zhang
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
| | - Yanfei Li
- School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Jue Li
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tongji University School of Medicine, Shanghai, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, China
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Jahanifar F, Astani A, Shekarforoosh S, Jamhiri M, Safari F, Zarei F, Safari F. 1.25 Dihydroxyvitamin D3 Attenuates Hypertrophy Markers in Cardiomyoblast H9c2 Cells: Evaluation of Sirtuin3 mRNA and Protein Level. INT J VITAM NUTR RES 2019; 89:144-151. [PMID: 30856082 DOI: 10.1024/0300-9831/a000469] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background: The cellular and molecular mechanisms of cardioprotective effects of Vitamin D are poorly understood. Given the essential role of sirtuin-3 (SIRT3) as an endogenous negative regulator of cardiac hypertrophy, this study was designed to investigate the effect of 1, 25-dihydroxyvitamin D3 (calcitriol) on hypertrophy markers and SIRT3 mRNA and protein levels following angiotensin II induced - hypertrophy in cardiomyoblast H9c2 cells. Methods: Rat cardiomyoblast H9c2 cells were treated for 48 hr with angiotensin II alone (Ang group) or in combination with 1, 10 and 100 nM of calcitriol (C + Ang groups). Intact cells served as control (Ctl). The cell area was measured using methylene blue staining. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and SIRT3 transcription levels were measured by real time RT-PCR. SIRT3 protein expression was evaluated using western blot technique. Results: The results showed that in Ang group cell size was increase by 128.4 ± 15% (P < 0.001 vs. Ctl) whereas in C100 + Ang group it was increased by 21.3 ± 6% (P < 0.001 vs. Ang group). Calcitriol pretreatment decreased ANP mRNA level significantly (P < 0.05) in comparison with Ang group (Ang: 75.5 ± 15%, C100 + Ang: 19.2 ± 9%). There were no significant differences between Ang group and cells pretreated with 1 and 10 nM of calcitriol. SIRT3 at mRNA and protein levels did not change significantly among the experimental groups. Conclusions: In conclusion, pretreatment with calcitriol (100 nM) prevents Ang II-induced hypertrophy in cardiomyoblast H9c2 cells. This probably occurs through other pathways except SIRT3 upregulation.
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Affiliation(s)
- Fatemeh Jahanifar
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Akram Astani
- Department of Microbiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Mohabbat Jamhiri
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Farideh Zarei
- Premature Neonates Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Safari
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Role of cardiac mast cells in exercise training-mediated cardiac remodeling in angiotensin II-infused ovariectomized rats. Life Sci 2019; 219:209-218. [PMID: 30658099 DOI: 10.1016/j.lfs.2019.01.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/03/2019] [Accepted: 01/13/2019] [Indexed: 01/03/2023]
Abstract
AIMS Regular exercise is recommended in postmenopausal women to prevent the development of heart disease, but mechanism underlying the protection is not completely understood. Many studies have suggested that exercise training notably mediated whole body immune and inflammatory functions. Whether exercise training prevents cardiac dysfunction after deprivation of female sex hormones by inhibiting cardiac immune activation is therefore interesting. MAIN METHODS Nine-week treadmill running program was introduced in sham-operated and ovariectomized rats. In addition, chronic angiotensin II infusion was further challenged to activate pathological cardiac remodeling. Cardiac remodeling in associated with the density and degranulation of cardiac mast cells was then evaluated. KEY FINDINGS With exogenous angiotensin II-induced hypertension, cardiac hypertrophy with myocardial fibrosis was shown similarly in both sham-operated controls and ovariectomized rats. Although exercise training did not prevent cardiac hypertrophy, myocardial fibrosis was abolished by exercise. While ovariectomy increased both cardiac mast cell density and degranulation percentage, angiotensin II infusion only enhanced mast cell density. Exercise training could not decrease the density of mast cells, but it did normalize the percentage of degranulation in all groups. Correlation analysis suggested that cardiac mast cell activation is inversely associated with cardiomyocyte hypertrophy due to exercise training but is directly correlated to cardiac hypertrophy by angiotensin II infusion. SIGNIFICANCE Exercise training could attenuate cardiac mast cell hyperactivation induced by either deprivation of female sex hormones or excessive angiotensin II. Additionally, cardiac mast cells could be a solution in the distinction between physiological and pathological hypertrophic development.
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10
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Kittana N. Angiotensin-converting enzyme 2-Angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment. Fundam Clin Pharmacol 2017; 32:14-25. [DOI: 10.1111/fcp.12318] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 08/17/2017] [Indexed: 01/28/2023]
Affiliation(s)
- Naim Kittana
- Department of Biomedical Sciences; An-Najah National University; New Campus, Pharmacy Building, 2nd Floor, Akademia Street, PO Box: 7 Nablus West-Bank Palestine
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11
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Pursani V, Pethe P, Bashir M, Sampath P, Tanavde V, Bhartiya D. Genetic and Epigenetic Profiling Reveals EZH2-mediated Down Regulation of OCT-4 Involves NR2F2 during Cardiac Differentiation of Human Embryonic Stem Cells. Sci Rep 2017; 7:13051. [PMID: 29026152 PMCID: PMC5638931 DOI: 10.1038/s41598-017-13442-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 09/25/2017] [Indexed: 02/07/2023] Open
Abstract
Human embryonic (hES) stem cells are widely used as an in vitro model to understand global genetic and epigenetic changes that occur during early embryonic development. In-house derived hES cells (KIND1) were subjected to directed differentiation into cardiovascular progenitors (D12) and beating cardiomyocytes (D20). Transcriptome profiling of undifferentiated (D0) and differentiated (D12 and 20) cells was undertaken by microarray analysis. ChIP and sequential ChIP were employed to study role of transcription factor NR2F2 during hES cells differentiation. Microarray profiling showed that an alteration of about 1400 and 1900 transcripts occurred on D12 and D20 respectively compared to D0 whereas only 19 genes were altered between D12 and D20. This was found associated with corresponding expression pattern of chromatin remodelers, histone modifiers, miRNAs and lncRNAs marking the formation of progenitors and cardiomyocytes on D12 and D20 respectively. ChIP sequencing and sequential ChIP revealed the binding of NR2F2 with polycomb group member EZH2 and pluripotent factor OCT4 indicating its crucial involvement in cardiac differentiation. The study provides a detailed insight into genetic and epigenetic changes associated with hES cells differentiation into cardiac cells and a role for NR2F2 is deciphered for the first time to down-regulate OCT-4 via EZH2 during cardiac differentiation.
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Affiliation(s)
- Varsha Pursani
- Stem Cell Biology Department, ICMR- National Institute for Research in Reproductive Health, Mumbai, 400012, India
| | - Prasad Pethe
- Stem Cell Biology Department, ICMR- National Institute for Research in Reproductive Health, Mumbai, 400012, India
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS University, Mumbai, 400056, India
| | - Mohsin Bashir
- Institute of Medical Biology, Agency for Science Technology & Research (A*STAR), Singapore, 138648, Singapore
| | - Prabha Sampath
- Institute of Medical Biology, Agency for Science Technology & Research (A*STAR), Singapore, 138648, Singapore
| | - Vivek Tanavde
- Bioinformatics Institute, Agency for Science Technology & Research (A*STAR), Singapore, 138671, Singapore
- Division of Biological & Life Sciences, School of Arts & Sciences, Ahmedabad University, Ahmedabad, 380009, India
| | - Deepa Bhartiya
- Stem Cell Biology Department, ICMR- National Institute for Research in Reproductive Health, Mumbai, 400012, India.
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12
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Chistiakov DA, Orekhov AN, Bobryshev YV. Treatment of cardiovascular pathology with epigenetically active agents: Focus on natural and synthetic inhibitors of DNA methylation and histone deacetylation. Int J Cardiol 2016; 227:66-82. [PMID: 27852009 DOI: 10.1016/j.ijcard.2016.11.204] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/06/2016] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease (CVD) retains a leadership as a major cause of human death worldwide. Although a substantial progress was attained in the development of cardioprotective and vasculoprotective drugs, a search for new efficient therapeutic strategies and promising targets is under way. Modulation of epigenetic CVD mechanisms through administration epigenetically active agents is one of such new approaches. Epigenetic mechanisms involve heritable changes in gene expression that are not linked to the alteration of DNA sequence. Pathogenesis of CVDs is associated with global genome-wide changes in DNA methylation and histone modifications. Epigenetically active compounds that influence activity of epigenetic modulators such as DNA methyltransferases (DNMTs), histone acetyltransferases, histone deacetylases (HDACs), etc. may correct these pathogenic changes in the epigenome and therefore be used for CVD therapy. To date, many epigenetically active natural substances (such as polyphenols and flavonoids) and synthetic compounds such as DNMT inhibitors or HDAC inhibitors are known. Both native and chemical DNMT and HDAC inhibitors possess a wide range of cytoprotective activities such as anti-inflammatory, antioxidant, anti-apoptotic, anti-anfibrotic, and anti-hypertrophic properties, which are beneficial of treatment of a variety of CVDs. However, so far, only synthetic DNMT inhibitors enter clinical trials while synthetic HDAC inhibitors are still under evaluation in preclinical studies. In this review, we consider epigenetic mechanisms such as DNA methylation and histone modifications in cardiovascular pathology and the epigenetics-based therapeutic approaches focused on the implementation of DNMT and HDAC inhibitors.
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Affiliation(s)
- Dimitry A Chistiakov
- Department of Molecular Genetic Diagnostics and Cell Biology, Division of Laboratory Medicine, Institute of Pediatrics, Research Center for Children's Health, 119991, Moscow, Russia
| | - Alexander N Orekhov
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia; Department of Biophysics, Biological Faculty, Moscow State University, Moscow, 119991, Russia; Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, 121609, Russia; National Research Center for Preventive Medicine, Moscow, 101000, Russia
| | - Yuri V Bobryshev
- Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow, 125315, Russia; Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; School of Medicine, University of Western Sydney, Campbelltown, NSW 2560, Australia.
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13
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Gopi V, Subramanian V, Manivasagam S, Vellaichamy E. Angiotensin II down-regulates natriuretic peptide receptor-A expression and guanylyl cyclase activity in H9c2 (2-1) cardiac myoblast cells: Role of ROS and NF-κB. Mol Cell Biochem 2015. [DOI: 10.1007/s11010-015-2513-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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14
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Yang JY, Wang Q, Wang W, Zeng LF. Histone deacetylases and cardiovascular cell lineage commitment. World J Stem Cells 2015; 7:852-858. [PMID: 26131315 PMCID: PMC4478631 DOI: 10.4252/wjsc.v7.i5.852] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/14/2015] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVDs), which include all diseases of the heart and circulation system, are the leading cause of deaths on the globally. During the development of CVDs, choric inflammatory, lipid metabolism disorder and endothelial dysfunction are widely recognized risk factors. Recently, the new treatment for CVDs that designed to regenerate the damaged myocardium and injured vascular endothelium and improve recovery by the use of stem cells, attracts more and more public attention. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from lysine residues of histone proteins allowing the histones to wrap the DNA more tightly and commonly known as epigenetic regulators of gene transcription. HDACs play indispensable roles in nearly all biological processes, such as transcriptional regulation, cell cycle progression and developmental events, and have originally shown to be involved in cancer and neurological diseases. HDACs are also found to play crucial roles in cardiovascular diseases by modulating vascular cell homeostasis (e.g., proliferation, migration, and apoptosis of both ECs and SMCs). This review focuses on the roles of different members of HDACs and HDAC inhibitor on stem cell/ progenitor cell differentiation toward vascular cell lineages (endothelial cells, smooth muscle cells and Cardiomyocytes) and its potential therapeutics.
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15
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Cattaneo M, Baronchelli S, Schiffer D, Mellai M, Caldera V, Saccani GJ, Dalpra L, Daga A, Orlandi R, DeBlasio P, Biunno I. Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid. J Biol Chem 2013; 289:2826-38. [PMID: 24311781 DOI: 10.1074/jbc.m113.527754] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.
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Affiliation(s)
- Monica Cattaneo
- From the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy
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16
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Simple autogeneic feeder cell preparation for pluripotent stem cells. Stem Cell Res 2011; 6:83-9. [DOI: 10.1016/j.scr.2010.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 09/21/2010] [Accepted: 09/21/2010] [Indexed: 11/18/2022] Open
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17
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Odenbach J, Wang X, Cooper S, Chow FL, Oka T, Lopaschuk G, Kassiri Z, Fernandez-Patron C. MMP-2 mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and TACE. Hypertension 2010; 57:123-30. [PMID: 21079048 DOI: 10.1161/hypertensionaha.110.159525] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Development of cardiovascular disease induced by excessive Gq protein-coupled receptor agonist stimulation depends on signaling networks involving multiple matrix metalloproteinases (MMPs) and metalloproteinase disintegrins (ADAMs). Here, we hypothesized that MMP-2, being a major gelatinase in cardiac and vascular tissue, was likely to play a key role in cardiovascular homeostasis. We targeted MMP-2 using complementary and overlapping approaches involving pharmacological inhibition and RNA interference in mice treated with angiotensin II (1.4 mg/kg per day) for 12 days. We studied the development of hypertension (by tail cuff plethysmography), cardiac hypertrophy (by M-mode echocardiography, cardiomyocyte cross-sectional area, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis of hypertrophy marker genes), and fibrosis (by picrosirius red collagen staining and qRT-PCR analysis of fibrosis marker genes) in mice receiving angiotensin II. We found that angiotensin II infusion upregulated MMP-2 concurrent with the development of hypertension, hypertrophy, and fibrosis. This upregulation of MMP-2 depended on MMP-7 and TACE (tumor necrosis factor-α convertase, ADAM-17). RNA interference targeting MMP-7 and TACE attenuated the angiotensin II-induced upregulation of MMP-2 and prevented the development of hypertension, as well as development of cardiac hypertrophy and fibrosis. In contrast, pharmacological inhibition and RNA interference of MMP-2 attenuated angiotensin II-induced hypertension, without influencing development of cardiac hypertrophy or fibrosis. Downstream of MMP-7 and TACE, MMP-2 mediated angiotensin II-induced hypertension, but did not mediate cardiac hypertrophy or fibrosis. This suggests a functional specialization of MMP-2 in agonist-induced cardiovascular disease development that has potential implications for the design of metalloproteinase-based therapeutic strategies.
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Affiliation(s)
- Jeffrey Odenbach
- Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
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18
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Cardinale JP, Sriramula S, Pariaut R, Guggilam A, Mariappan N, Elks CM, Francis J. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension 2010; 56:437-44. [PMID: 20679181 DOI: 10.1161/hypertensionaha.110.154567] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species and proinflammatory cytokines contribute to cardiovascular diseases. Inhibition of downstream transcription factors and gene modifiers of these components are key mediators of hypertensive response. Histone acetylases/deacetylases can modulate the gene expression of these hypertrophic and hypertensive components. Therefore, we hypothesized that long-term inhibition of histone deacetylase with valproic acid might attenuate hypertrophic and hypertensive responses by modulating reactive oxygen species and proinflammatory cytokines in SHR rats. Seven-week-old SHR and WKY rats were used in this study. Following baseline blood pressure measurement, rats were administered valproic acid in drinking water (0.71% wt/vol) or vehicle, with pressure measured weekly thereafter. Another set of rats were treated with hydralazine (25 mg/kg per day orally) to determine the pressure-independent effects of HDAC inhibition on hypertension. Following 20 weeks of treatment, heart function was measured using echocardiography, rats were euthanized, and heart tissue was collected for measurement of total reactive oxygen species, as well as proinflammatory cytokine, cardiac hypertrophic, and oxidative stress gene and protein expressions. Blood pressure, proinflammatory cytokines, hypertrophic markers, and reactive oxygen species were increased in SHR versus WKY rats. These changes were decreased in valproic acid-treated SHR rats, whereas hydralazine treatment only reduced blood pressure. These data indicate that long-term histone deacetylase inhibition, independent of the blood pressure response, reduces hypertrophic, proinflammatory, and hypertensive responses by decreasing reactive oxygen species and angiotensin II type1 receptor expression in the heart, demonstrating the importance of uncontrolled histone deacetylase activity in hypertension.
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Affiliation(s)
- Jeffrey P Cardinale
- Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
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Abstract
Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-to-mesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs.
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Affiliation(s)
- Erik W Bush
- Gilead Colorado Inc, 3333 Walnut St, Boulder, CO 80301, USA.
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