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      Age-related changes in mineralocorticoid receptors in rat hearts

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          Abstract

          Age-related alterations in the renin-angiotensin-aldosterone system (RAAS) have been reported in the cardiovascular system; however, the detailed mechanism of the RAAS component mineralocorticoid receptors (MR) has not been elucidated. The present study aimed to investigate the associations between MR and cardiac aging in rats, as well as the regulatory effects of oxidative stress and mitochondrial abnormalities in the aging process. MR expression in the hearts of male Sprague-Dawley rats aged 3 months (young rats) and 24 months (old rats) was evaluated in vivo. In addition, in vitro, H9C2 cells were treated with a specific MR antagonist, eplerenone, in order to investigate the molecular mechanism underlying the inhibition of myocyte aging process. The results demonstrated that MR expression was significantly higher in 24-month-old rat hearts compared with in 3-month-old rat hearts. These changes were accompanied by increased p53 expression, decreased peroxisome proliferator-activated receptor γ coactivator-1α expression, decreased mitochondrial renewal as assessed by electron microscopy, increased oxidative stress and decreased superoxide dismutase. In vitro, selective antagonism of MR partially blocked H 2O 2-induced myocardial aging as assessed by p16, p21 and p53 expression levels and excessive reactive oxygen species (ROS) accumulation. These results indicated that increased MR expression may drive age-related cardiac dysfunction via mitochondrial damage, increased ROS accumulation and an imbalanced redox state.

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          Telomere dysfunction induces metabolic and mitochondrial compromise.

          Ergun Sahin, Simona Colla, Marc Liesa … (2011)
          Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
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            Ageing, neurodegeneration and brain rejuvenation.

            Tony Wyss-Coray (2016)
            Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.
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              Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.

              J. J. LEHMAN, P M Barger, A. Kovács … (2000)
              Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Med Rep
                Journal ID (iso-abbrev): Mol Med Rep
                Title: Molecular Medicine Reports
                Publisher: D.A. Spandidos
                ISSN (Print): 1791-2997
                ISSN (Electronic): 1791-3004
                Publication date (Print): September 2020
                Publication date (Electronic): 19 June 2020
                Publication date PMC-release: 19 June 2020
                Volume: 22
                Issue: 3
                Pages: 1859-1867
                Affiliations
                [1 ]National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China
                [2 ]Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
                [3 ]Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
                [4 ]Department of Internal Medicine, Division of Cardiology, General Hospital of Puyang Oil Field, Puyang, Henan 457001, P.R. China
                [5 ]Department of Internal Medicine, Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
                [6 ]Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, Hubei 430030, P.R. China
                Author notes
                Correspondence to: Dr Ling Tu, Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, P.R. China, E-mail: lingtu@ 123456tjh.tjmu.edu.cn
                Dr Xizhen Xu, Department of Internal Medicine, Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, P.R. China, E-mail: xzxu@ 123456tjh.tjmu.edu.cn
                Article
                Publisher ID: mmr-22-03-1859
                DOI: 10.3892/mmr.2020.11260
                PMC ID: 7411371
                PubMed ID: 32582979
                SO-VID: 5e51e3d0-b876-4d04-98d2-820009693645
                Copyright © Copyright: © Hu et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 26 January 2018
                Date accepted : 04 July 2019
                Categories
                Subject: Articles

                Keywords: mineralocorticoid receptors,cardiac aging,oxidative stress,mitochondrial dysfunction,redox state
                Data availability:
                Keywords: mineralocorticoid receptors, cardiac aging, oxidative stress, mitochondrial dysfunction, redox state

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