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The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 51763

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Prof. Satoru Eguchi

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Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Interests: cardiovascular signaling; angiotensin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The renin angiotensin system (RAS) plays a key role in blood pressure regulation by controlling vascular smooth muscle constriction and renal water/sodium reabsorption. Disruption of RAS regulation occurs in individuals with cardiovascular disease (CVD) risk factors, leading to hypertension and associated complications. Aging is one of the major nonmodifiable risk factors for hypertension and other CVDs, which is exemplified in middle age individuals whose vasculature is more prematurely aged than that of their chronologically aged counterparts, and who therefore suffer from CVD development sooner. Recent research suggests that over-reactivity of the RAS plays a critical role in the pathogenesis of an accelerated aging phenotype seen in various diseases, such as neurodegenerative, cardiovascular, and metabolic disorders. While the exact mechanism by which RAS contributes to the development of these pathologies is not clear, it likely involves induction of premature senescence and senescence associated secretory phenotype (SASP). Disruption of organelle (i.e., mitochondria) quality control and proteostasis may also be affected in senescence-associated diseases, as these decline with age. Therefore, elucidating the molecular mechanism of the premature aging phenotype induced by the RAS would likely provide potential new therapeutic opportunities to maintain healthy aging and reduce the economic burden of aging diseases in the next century. Accordingly, the topics of this Special Issue include but are not limited to the recent findings in molecular mechanisms of the RAS in cellular aging, how the RAS influences age-related cardiovascular, metabolic, and neurological disorders, and translational evaluations on the findings.

Prof. Satoru Eguchi
Guest Editor

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Keywords

Senescence
Biological aging
Early vascular aging (EVA)
Aortic stiffness
Senolytics
Longevity
Mitochondria
Proteotoxicity

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Published Papers (11 papers)

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Research

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18 pages, 1791 KiB

Open AccessArticle

Angiotensin-(1-7) Prevents Lipopolysaccharide-Induced Autophagy via the Mas Receptor in Skeletal Muscle

by Juan Carlos Rivera, Johanna Abrigo, Franco Tacchi, Felipe Simon, Enrique Brandan, Robson A. Santos, Michael Bader, Mario Chiong and Claudio Cabello-Verrugio

Int. J. Mol. Sci. 2020, 21(24), 9344; https://doi.org/10.3390/ijms21249344 - 8 Dec 2020

Cited by 8 | Viewed by 3671

Abstract

Skeletal muscle atrophy, which occurs in lipopolysaccharide (LPS)-induced sepsis, causes a severe muscle function reduction. The increased autophagy contributes to sepsis-induced skeletal muscle atrophy in a model of LPS injection, increasing LC3II/LC3I ratio, autophagy flux, and autophagosomes. Angiotensin-(1-7) (Ang-(1-7)) has anti-atrophic effects via the Mas receptor in skeletal muscle. However, the impact of Ang-(1-7) on LPS-induced autophagy is unknown. In this study, we determined the effect of Ang-(1-7) on sepsis-induced muscle autophagy. C57BL6 wild-type (WT) mice and mice lacking the Mas receptor (KO Mas) were injected with LPS together with the systemic administration of Ang-(1-7) to determine autophagy in skeletal muscle. We also evaluated autophagy and p38 and c-Jun N-terminal kinase (JNK)activation. Our results show that Ang-(1-7) prevents LPS-induced autophagy in the diaphragm, tibialis anterior, and gastrocnemius of WT mice, which is demonstrated by a decrease in the LC3II/LC3I ratio and mRNA levels of lc3b and ctsl. This effect was lost in KO Mas mice, suggesting the role of the Mas receptor. The results in C2C12 cells show that Ang-(1-7) reduces several LPS-dependent effects, such as autophagy (LC3II/LC3I ratio, autophagic flux, and autophagosomes), activation of p38 and JNK, B-cell lymphoma-2 (BCL2) phosphorylation, and disassembly of the Beclin1/BCL2 complex. In conclusion, Ang-(1-7)/Mas receptor reduces LPS-induced autophagy in skeletal muscle. In vitro assays indicate that Ang-(1-7) prevents LPS-induced autophagy and modifies the MAPK signaling and the disassembly of a complex involved at the beginning of autophagy. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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13 pages, 1758 KiB

Open AccessArticle

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice

by Amanda J. Miller, Sarah S. Bingaman, Darren Mehay, Daniela Medina and Amy C. Arnold

Int. J. Mol. Sci. 2020, 21(14), 5131; https://doi.org/10.3390/ijms21145131 - 20 Jul 2020

Cited by 11 | Viewed by 3196

Abstract

Angiotensin (Ang)-(1-7) is a beneficial renin–angiotensin system (RAS) hormone that elicits protective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic syndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging, however, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related elevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged (16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a subcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body composition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment. Adipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene expression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic and mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved insulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body composition. The blood pressure–lowering effects of Ang-(1-7) in aged mice were associated with reduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic risk. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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12 pages, 1946 KiB

Open AccessCommunication

78 kDa Glucose-Regulated Protein Attenuates Protein Aggregation and Monocyte Adhesion Induced by Angiotensin II in Vascular Cells

by Stephanie Cicalese, Keisuke Okuno, Katherine J. Elliott, Tatsuo Kawai, Rosario Scalia, Victor Rizzo and Satoru Eguchi

Int. J. Mol. Sci. 2020, 21(14), 4980; https://doi.org/10.3390/ijms21144980 - 15 Jul 2020

Cited by 12 | Viewed by 2825

Abstract

Investigations of vascular smooth muscle cell (VSMC) phenotypic modulation due to angiotensin II (AngII) stimulation are important for understanding molecular mechanisms contributing to hypertension and associated vascular pathology. AngII induces endoplasmic reticulum (ER) stress in VSMCs, which has been implicated in hypertensive vascular remodeling. Under ER stress, 78 kDa glucose-regulated protein (GRP78) acts as an endogenous chaperone, as well as a master controller of unfolded protein response (UPR) to maintain protein quality control. However, the potential downstream consequences of ER stress induced by AngII on protein quality control and pro-inflammatory phenotype in VSMCs remain elusive. This study aims to identify protein aggregation as evidence of the disruption of protein quality control in VSMCs, and to test the hypothesis that preservation of proteostasis by overexpression of GRP78 can attenuate the AngII-induced pro-inflammatory phenotype in VSMCs. Increases in protein aggregation and enhanced UPR were observed in VSMCs exposed to AngII, which were mitigated by overexpression of GRP78. Moreover, GRP78 overexpression attenuated enhanced monocyte adhesion to VSMCs induced by AngII. Our results thus indicate that the prevention of protein aggregation can potentially mitigate an inflammatory phenotype in VSMCs, which may suggest an alternative therapy for the treatment of AngII-associated vascular disorders. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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17 pages, 5095 KiB

Open AccessArticle

The Protective Effect of Chlorogenic Acid on Vascular Senescence via the Nrf2/HO-1 Pathway

by Yoshiko Hada, Haruhito A. Uchida, Nozomu Otaka, Yasuhiro Onishi, Shugo Okamoto, Mariko Nishiwaki, Rika Takemoto, Hidemi Takeuchi and Jun Wada

Int. J. Mol. Sci. 2020, 21(12), 4527; https://doi.org/10.3390/ijms21124527 - 25 Jun 2020

Cited by 38 | Viewed by 3715

Abstract

The world faces the serious problem of aging. In this study, we aimed to investigate the effect of chlorogenic acid (CGA) on vascular senescence. C57/BL6 female mice that were 14 ± 3 months old were infused with either Angiotensin II (AngII) or saline subcutaneously for two weeks. These mice were administered CGA of 20 or 40 mg/kg/day, or saline via oral gavage. AngII infusion developed vascular senescence, which was confirmed by senescence associated-β-galactosidase (SA-β-gal) staining. CGA administration attenuated vascular senescence in a dose-dependent manner, in association with the increase of Sirtuin 1 (Sirt1) and endothelial nitric oxide synthase (eNOS), and with the decrease of p-Akt, PAI-1, p53, and p21. In an in vitro study, with or without pre-treatment of CGA, Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with H₂O₂ for an hour, then cultured in the absence or presence of 0.5–5.0 μM CGA for the indicated time. Endothelial cell senescence was induced by H₂O₂, which was attenuated by CGA treatment. Pre-treatment of CGA increased Nrf2 in HUVECs. After H₂O₂ treatment, translocation of Nrf2 into the nucleus and the subsequent increase of Heme Oxygenase-1 (HO-1) were observed earlier in CGA-treated cells. Furthermore, the HO-1 inhibitor canceled the beneficial effect of CGA on vascular senescence in mice. In conclusion, CGA exerts a beneficial effect on vascular senescence, which is at least partly dependent on the Nuclear factor erythroid 2-factor 2 (Nrf2)/HO-1 pathway. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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16 pages, 2619 KiB

Open AccessArticle

Protective Effect of Angiotensin 1–7 on Sarcopenia Induced by Chronic Liver Disease in Mice

by Francisco Aguirre, Johanna Abrigo, Francisco Gonzalez, Andrea Gonzalez, Felipe Simon and Claudio Cabello-Verrugio

Int. J. Mol. Sci. 2020, 21(11), 3891; https://doi.org/10.3390/ijms21113891 - 29 May 2020

Cited by 15 | Viewed by 3559

Abstract

Sarcopenia associated with chronic liver disease (CLD) is one of the more common extrahepatic features in patients with these pathologies. Among the cellular alterations observed in the muscle tissue under CLD is the decline in the muscle strength and function, as well as the increased fatigue. Morphological changes, such as a decrease in the fiber diameter and transition in the fiber type, are also reported. At the molecular level, sarcopenia for CLD is characterized by: (i) a decrease in the sarcomeric protein, such as myosin heavy chain (MHC); (ii) an increase in the ubiquitin–proteasome system markers, such as atrogin-1/MAFbx1 and MuRF-1/TRIM63; (iii) an increase in autophagy markers, such as LC3II/LC3I ratio. Among the regulators of muscle mass is the renin-angiotensin system (RAS). The non-classical axis of RAS includes the Angiotensin 1–7 [Ang-(1-7)] peptide and its receptor Mas, which in skeletal muscle has anti-atrophic effect in models of muscle wasting induced by immobilization, lipopolysaccharide, myostatin or angiotensin II. In this paper, we evaluated the effect of Ang-(1-7) on the sarcopenia by CLD in a murine model induced by the 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hepatotoxin administered through diet. Our results show that Ang-(1-7) administration prevented the decline of the function and strength of muscle and increased the fatigue detected in the DDC-fed mice. Besides, we observed that the decreased fiber diameter and MHC levels, as well as the transition of fiber types, were all abolished by Ang-(1-7) in mice fed with DDC. Finally, Ang-(1-7) can decrease the atrogin-1 and MuRF-1 expression as well as the autophagy marker in mice treated with DDC. Together, our data support the protective role of Ang-(1-7) on the sarcopenia by CLD in mice. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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13 pages, 11806 KiB

Open AccessCommunication

Involvement of Senescence and Mitochondrial Fission in Endothelial Cell Pro-Inflammatory Phenotype Induced by Angiotensin II

by Masashi Miyao, Stephanie Cicalese, Tatsuo Kawai, Hannah A. Cooper, Michael J. Boyer, Katherine J. Elliott, Steven J. Forrester, Ryohei Kuroda, Victor Rizzo, Tomoki Hashimoto, Rosario Scalia and Satoru Eguchi

Int. J. Mol. Sci. 2020, 21(9), 3112; https://doi.org/10.3390/ijms21093112 - 28 Apr 2020

Cited by 29 | Viewed by 4387

Abstract

Angiotensin II (AngII) has a crucial role in cardiovascular pathologies, including endothelial inflammation and premature vascular aging. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. Here, we have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence assessed by senescence-associated β galactosidase activity. The number of β galactosidase-positive ECs induced by AngII was attenuated by treatment with a senolytic drug ABT737 or the chemical chaperone 4-phenylbutyrate. Monocyte adhesion assay revealed that the pro-inflammatory phenotype in ECs induced by AngII was alleviated by these treatments. AngII stimulation also increased mitochondrial fission in ECs, which was mitigated by mitochondrial division inhibitor-1. Pretreatment with mitochondrial division inhibitor-1 attenuated AngII-induced senescence and monocyte adhesion in ECs. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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15 pages, 4153 KiB

Open AccessArticle

Angiotensin (1-7) Decreases Myostatin-Induced NF-κB Signaling and Skeletal Muscle Atrophy

by Javier Aravena, Johanna Abrigo, Francisco Gonzalez, Francisco Aguirre, Andrea Gonzalez, Felipe Simon and Claudio Cabello-Verrugio

Int. J. Mol. Sci. 2020, 21(3), 1167; https://doi.org/10.3390/ijms21031167 - 10 Feb 2020

Cited by 28 | Viewed by 4931

Abstract

Myostatin is a myokine that regulates muscle function and mass, producing muscle atrophy. Myostatin induces the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. The main pathway that mediates protein degradation during muscle atrophy is the ubiquitin proteasome system, by increasing the expression of atrogin-1 and MuRF-1. In addition, myostatin activates the NF-κB signaling pathway. Renin–angiotensin system (RAS) also regulates muscle mass. Angiotensin (1-7) (Ang-(1-7)) has anti-atrophic properties in skeletal muscle. In this paper, we evaluated the effect of Ang-(1-7) on muscle atrophy and signaling induced by myostatin. The results show that Ang-(1-7) prevented the decrease of the myotube diameter and myofibrillar protein levels induced by myostatin. Ang-(1-7) also abolished the increase of myostatin-induced reactive oxygen species production, atrogin-1, MuRF-1, and TNF-α gene expressions and NF-κB signaling activation. Ang-(1-7) inhibited the activity mediated by myostatin through Mas receptor, as is demonstrated by the loss of all Ang-(1-7)-induced effects when the Mas receptor antagonist A779 was used. Our results show that the effects of Ang-(1-7) on the myostatin-dependent muscle atrophy and signaling are blocked by MK-2206, an inhibitor of Akt/PKB. Together, these data indicate that Ang-(1-7) inhibited muscle atrophy and signaling induced by myostatin through a mechanism dependent on Mas receptor and Akt/PKB. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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Review

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18 pages, 1395 KiB

Open AccessReview

SARS-CoV-2/Renin–Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle

by Andrea Gonzalez, Josué Orozco-Aguilar, Oscar Achiardi, Felipe Simon and Claudio Cabello-Verrugio

Int. J. Mol. Sci. 2020, 21(21), 7904; https://doi.org/10.3390/ijms21217904 - 24 Oct 2020

Cited by 25 | Viewed by 4441

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has produced significant health emergencies worldwide, resulting in the declaration by the World Health Organization of the coronavirus disease 2019 (COVID-19) pandemic. Acute respiratory syndrome seems to be the most common manifestation of COVID-19. A high proportion of patients require intensive care unit admission and mechanical ventilation (MV) to survive. It has been well established that angiotensin-converting enzyme type 2 (ACE2) is the primary cellular receptor for SARS-CoV-2. ACE2 belongs to the renin–angiotensin system (RAS), composed of several peptides, such as angiotensin II (Ang II) and angiotensin (1-7) (Ang-(1-7)). Both peptides regulate muscle mass and function. It has been described that SARS-CoV-2 infection, by direct and indirect mechanisms, affects a broad range of organ systems. In the skeletal muscle, through unbalanced RAS activity, SARS-CoV-2 could induce severe consequences such as loss of muscle mass, strength, and physical function, which will delay and interfere with the recovery process of patients with COVID-19. This article discusses the relationship between RAS, SARS-CoV-2, skeletal muscle, and the potentially harmful consequences for skeletal muscle in patients currently infected with and recovering from COVID-19. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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17 pages, 1710 KiB

Open AccessReview

Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics

by Keisuke Okuno, Stephanie Cicalese, Katherine J. Elliott, Tatsuo Kawai, Tomoki Hashimoto and Satoru Eguchi

Int. J. Mol. Sci. 2020, 21(18), 6579; https://doi.org/10.3390/ijms21186579 - 9 Sep 2020

Cited by 16 | Viewed by 5141

Abstract

Cardiovascular disease (CVD) is a prevalent issue in the global aging population. Premature vascular aging such as elevated arterial stiffness appears to be a major risk factor for CVD. Vascular smooth muscle cells (VSMCs) are one of the essential parts of arterial pathology and prone to stress-induced senescence. The pervasiveness of senescent VSMCs in the vasculature increases with age and can be further expedited by various stressing events such as oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and chronic inflammation. Angiotensin II (AngII) can induce many of these responses in VSMCs and is thus considered a key regulator of VSMC senescence associated with CVD. Understanding the precise mechanisms and consequences of senescent cell accumulation may uncover a new generation of therapies including senolytic and senomorphic compounds against CVD. Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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16 pages, 863 KiB

Open AccessReview

Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology

by Amanda St. Paul, Cali B. Corbett, Rachael Okune and Michael V. Autieri

Int. J. Mol. Sci. 2020, 21(12), 4525; https://doi.org/10.3390/ijms21124525 - 25 Jun 2020

Cited by 26 | Viewed by 10376

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in the Western and developing world, and the incidence of cardiovascular disease is increasing with the longer lifespan afforded by our modern lifestyle. Vascular diseases including coronary heart disease, high blood pressure, and stroke comprise the majority of cardiovascular diseases, and therefore represent a significant medical and socioeconomic burden on our society. It may not be surprising that these conditions overlap and potentiate each other when we consider the many cellular and molecular similarities between them. These intersecting points are manifested in clinical studies in which lipid lowering therapies reduce blood pressure, and anti-hypertensive medications reduce atherosclerotic plaque. At the molecular level, the vascular smooth muscle cell (VSMC) is the target, integrator, and effector cell of both atherogenic and the major effector protein of the hypertensive signal Angiotensin II (Ang II). Together, these signals can potentiate each other and prime the artery and exacerbate hypertension and atherosclerosis. Therefore, VSMCs are the fulcrum in progression of these diseases and, therefore, understanding the effects of atherogenic stimuli and Ang II on the VSMC is key to understanding and treating atherosclerosis and hypertension. In this review, we will examine studies in which hypertension and atherosclerosis intersect on the VSMC, and illustrate common pathways between these two diseases and vascular aging. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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14 pages, 951 KiB

Open AccessReview

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

by Fatima Y. Noureddine, Raffaele Altara, Fan Fan, Andriy Yabluchanskiy, George W. Booz and Fouad A. Zouein

Int. J. Mol. Sci. 2020, 21(12), 4268; https://doi.org/10.3390/ijms21124268 - 16 Jun 2020

Cited by 21 | Viewed by 4743 | Correction

Abstract

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia. Full article

(This article belongs to the Special Issue The Renin Angiotensin System, Molecular, Geroscience and Aging-Related Disorders)

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