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Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease
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Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (21 December 2018) | Viewed by 57713

Special Issue Editors

Prof. Dr. Jaap A. Joles

E-Mail Website
Guest Editor
Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands
Interests: cardiorenal syndrome; uremic animal models; regenerative nephrology; renal hypoxia; gasotransmitters; developmental renal programming; diabetic kidney disease; portable dialysis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Harry van Goor

E-Mail Website
Guest Editor
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
Interests: oxidative stress; biomarkers; thiosulfate; hydrogen sulfide
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gasotransmitters (NO, CO and H2S) play a central role in signal transduction via guanylate cyclase and cGMP in many tissues. Generally, their effects are vasodilatory, anti-inflammatory and anti-fibrotic. Moreover, all three inhibit mitochondrial respiration. Well-known pharmacological strategies involving NO include NO-donors for pulmonary hypertension and phosphodiesterase-inhibitors for erectile dysfunction. Sodium thiosulfate, is an H2S donor that appears useful in calciphylaxis in end-stage kidney disease. Therapeutic use of CO, for instance with CO-donors, is in its infancy. This Special Issue focuses on “Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease”. Different donor compounds have a wide range of kinetics. Various compounds target signalling pathways. Tolerance is well-recognised for NO-donors but has barely been addressed for CO and H2S. The interdependency of cardiac, renal and vascular function, as well as their involvement in systemic conditions, such as diabetes and pre-eclampsia, encourage an integrative systems approach. Original studies (preclinical and clinical), with an emphasis on molecular biology and molecular medicine, as well as reviews, are all welcome.

Prof. Dr. Jaap A. Joles
Prof. Dr. Harry van Goor
Guest Editors

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Keywords

  •  nitric oxide
  •  carbon monoxide
  •  hydrogen sulfide
  •  guanylate cyclase
  •  hypertension
  •  chronic kidney disease
  •  heart failure
  •  atherosclerosis

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Published Papers (9 papers)

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Research

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12 pages, 2308 KiB  
Article
Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide
by Rafael Ramirez-Carracedo, Laura Tesoro, Ignacio Hernandez, Javier Diez-Mata, Marco Filice, Rocío Toro, Manuel Rodriguez-Piñero, Jose Luis Zamorano, Marta Saura and Carlos Zaragoza
Int. J. Mol. Sci. 2018, 19(10), 3248; https://doi.org/10.3390/ijms19103248 - 19 Oct 2018
Cited by 22 | Viewed by 4892
Abstract
Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early [...] Read more.
Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early plaque formation and enlargement. We found increased levels of MMP-9 and MMP-13 in human endarterectomies with advanced atherosclerosis, together with significant amounts of extracellular matrix (ECM) metalloproteinase inducer EMMPRIN. To test whether the absence of NO may aggravate atherosclerosis through EMMPRIN activation, double NOS3/apoE knockout (KO) mice expressed high levels of EMMPRIN in carotid plaques, suggesting that targeting extracellular matrix degradation may represent a new mechanism by which endothelial NO prevents atherosclerosis. Based on our previous experience, by using gadolinium-enriched paramagnetic fluorescence micellar nanoparticles conjugated with AP9 (NAP9), an EMMPRIN-specific binding peptide, magnetic resonance sequences allowed non-invasive visualization of carotid EMMPRIN in NOS3/apoE over apoE control mice, in which atheroma plaques were significantly reduced. Taken together, these results point to EMMPRIN as a new therapeutic target of NO-mediated protection against atherosclerosis, and NAP9 as a non-invasive molecular tool to target atherosclerosis. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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12 pages, 2709 KiB  
Article
Exercise Training Has Contrasting Effects in Myocardial Infarction and Pressure Overload Due to Divergent Endothelial Nitric Oxide Synthase Regulation
by Elza D. Van Deel, Yanti Octavia, Monique C. De Waard, Martine De Boer and Dirk J. Duncker
Int. J. Mol. Sci. 2018, 19(7), 1968; https://doi.org/10.3390/ijms19071968 - 6 Jul 2018
Cited by 14 | Viewed by 3925
Abstract
The beneficial effects of exercise training (EX) on cardiac pathology are well recognized. Previously, we found that the effects of EX on cardiac dysfunction in mice critically depend on the underlying etiology. EX exerted beneficial effects after myocardial infarction (MI); however, cardiac pathology [...] Read more.
The beneficial effects of exercise training (EX) on cardiac pathology are well recognized. Previously, we found that the effects of EX on cardiac dysfunction in mice critically depend on the underlying etiology. EX exerted beneficial effects after myocardial infarction (MI); however, cardiac pathology following pressure overload produced by transverse aortic constriction (TAC) was aggravated by EX. In the presented study, we investigated whether the contrasting effects of EX on cardiac dysfunction can be explained by an etiology-specific response of endothelial nitric oxide (NO) synthase (eNOS) to EX, which divergently affects the balance between nitric oxide and superoxide. For this purpose, mice were exposed to eight weeks of voluntary wheel running or sedentary housing (SED), immediately after sham, MI, or TAC surgery. Left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements. EX ameliorated LV dysfunction and remodeling after MI, but not following TAC, in which EX even aggravated fibrosis. Strikingly, EX attenuated superoxide levels after MI, but exacerbated NOS-dependent superoxide levels following TAC. Similarly, elevated eNOS S-glutathionylation and eNOS monomerization, which were observed in both MI and TAC, were corrected by EX in MI, but aggravated by EX after TAC. Additionally, EX reduced antioxidant activity in TAC, while it was maintained following EX in MI. In conclusion, the present study shows that EX mitigates cardiac dysfunction after MI, likely by attenuating eNOS uncoupling-mediated oxidative stress, whereas EX tends to aggravate cardiac dysfunction following TAC, likely due to exacerbating eNOS-mediated oxidative stress. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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Review

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16 pages, 1382 KiB  
Review
Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development
by Micaela Gliozzi, Miriam Scicchitano, Francesca Bosco, Vincenzo Musolino, Cristina Carresi, Federica Scarano, Jessica Maiuolo, Saverio Nucera, Alessia Maretta, Sara Paone, Rocco Mollace, Stefano Ruga, Maria Caterina Zito, Roberta Macrì, Francesca Oppedisano, Ernesto Palma, Daniela Salvemini, Carolina Muscoli and Vincenzo Mollace
Int. J. Mol. Sci. 2019, 20(13), 3294; https://doi.org/10.3390/ijms20133294 - 4 Jul 2019
Cited by 150 | Viewed by 8253
Abstract
The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the [...] Read more.
The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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15 pages, 1474 KiB  
Review
Protective Smell of Hydrogen Sulfide and Polysulfide in Cisplatin-Induced Nephrotoxicity
by Xu Cao, Wencan Zhang, Philip K. Moore and Jinsong Bian
Int. J. Mol. Sci. 2019, 20(2), 313; https://doi.org/10.3390/ijms20020313 - 14 Jan 2019
Cited by 33 | Viewed by 5804
Abstract
Though historically known as a toxic gas, hydrogen sulfide (H2S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential [...] Read more.
Though historically known as a toxic gas, hydrogen sulfide (H2S) has displayed a new face as the third endogenous gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO). Here in this review, we survey the role and therapeutic potential of H2S in cisplatin-induced nephrotoxicity. Specifically, reduction of H2S by cystathionine γ-lyase (CSE) downregulation upon cisplatin treatment may contribute to cisplatin-induced renal cell injury, possibly by augmentation of endogenous reactive oxygen species (ROS) production, while H2S donation may prevent subsequent renal dysfunction by inhibiting NADPH oxidase activation. Intriguingly, H2S slow-releasing compound GYY4137 seems to increase the anticancer activity of cisplatin, at least in several cancer cell lines, and this is probably due to its own anticancer effect. However, the efficacy of H2S donors in tumor-bearing animals remains to be tested in terms of renal protection and cancer inhibition after receiving cisplatin. Furthermore, accumulative evidence regarding usage of polysulfide, a novel H2S derived molecule, in the therapy of cisplatin-induced nephrotoxicity, was also summarized. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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21 pages, 2259 KiB  
Review
Hydrogen Sulfide: A Therapeutic Option in Systemic Sclerosis
by Amaal Eman Abdulle, Harry Van Goor and Douwe J. Mulder
Int. J. Mol. Sci. 2018, 19(12), 4121; https://doi.org/10.3390/ijms19124121 - 19 Dec 2018
Cited by 15 | Viewed by 5691 | Correction
Abstract
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related [...] Read more.
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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23 pages, 918 KiB  
Review
Role of Nitric Oxide in the Cardiovascular and Renal Systems
by Ashfaq Ahmad, Sara K. Dempsey, Zdravka Daneva, Maleeha Azam, Ningjun Li, Pin-Lan Li and Joseph K. Ritter
Int. J. Mol. Sci. 2018, 19(9), 2605; https://doi.org/10.3390/ijms19092605 - 3 Sep 2018
Cited by 178 | Viewed by 11968
Abstract
The gasotransmitters are a family of gaseous signaling molecules which are produced endogenously and act at specific receptors to play imperative roles in physiologic and pathophysiologic processes. As a well-known gasotransmitter along with hydrogen sulfide and carbon monoxide, nitric oxide (NO) has earned [...] Read more.
The gasotransmitters are a family of gaseous signaling molecules which are produced endogenously and act at specific receptors to play imperative roles in physiologic and pathophysiologic processes. As a well-known gasotransmitter along with hydrogen sulfide and carbon monoxide, nitric oxide (NO) has earned repute as a potent vasodilator also known as endothelium-derived vasorelaxant factor (EDRF). NO has been studied in greater detail, from its synthesis and mechanism of action to its physiologic, pathologic, and pharmacologic roles in different disease states. Different animal models have been applied to investigate the beneficial effects of NO as an antihypertensive, renoprotective, and antihypertrophic agent. NO and its interaction with different systems like the renin–angiotensin system, sympathetic nervous system, and other gaseous transmitters like hydrogen sulfide are also well studied. However, links that appear to exist between the endocannabinoid (EC) and NO systems remain to be fully explored. Experimental approaches using modulators of its synthesis including substrate, donors, and inhibitors of the synthesis of NO will be useful for establishing the relationship between the NO and EC systems in the cardiovascular and renal systems. Being a potent vasodilator, NO may be unique among therapeutic options for management of hypertension and resulting renal disease and left ventricular hypertrophy. Inclusion of NO modulators in clinical practice may be useful not only as curatives for particular diseases but also for arresting disease prognoses through its interactions with other systems. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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18 pages, 1249 KiB  
Review
The Role of Midkine in Arteriogenesis, Involving Mechanosensing, Endothelial Cell Proliferation, and Vasodilation
by Ludwig T. Weckbach, Klaus T. Preissner and Elisabeth Deindl
Int. J. Mol. Sci. 2018, 19(9), 2559; https://doi.org/10.3390/ijms19092559 - 29 Aug 2018
Cited by 32 | Viewed by 4636
Abstract
Mechanical forces in blood circulation such as shear stress play a predominant role in many physiological and pathophysiological processes related to vascular responses or vessel remodeling. Arteriogenesis, defined as the growth of pre-existing arterioles into functional collateral arteries compensating for stenosed or occluded [...] Read more.
Mechanical forces in blood circulation such as shear stress play a predominant role in many physiological and pathophysiological processes related to vascular responses or vessel remodeling. Arteriogenesis, defined as the growth of pre-existing arterioles into functional collateral arteries compensating for stenosed or occluded arteries, is such a process. Midkine, a pleiotropic protein and growth factor, has originally been identified to orchestrate embryonic development. In the adult organism its expression is restricted to distinct tissues (including tumors), whereby midkine is strongly expressed in inflamed tissue and has been shown to promote inflammation. Recent investigations conferred midkine an important function in vascular remodeling and growth. In this review, we introduce the midkine gene and protein along with its cognate receptors, and highlight its role in inflammation and the vascular system with special emphasis on arteriogenesis, particularly focusing on shear stress-mediated vascular cell proliferation and vasodilatation. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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12 pages, 431 KiB  
Review
Therapeutic Aspects of Carbon Monoxide in Cardiovascular Disease
by Hyuk-Hoon Kim and Sangchun Choi
Int. J. Mol. Sci. 2018, 19(8), 2381; https://doi.org/10.3390/ijms19082381 - 13 Aug 2018
Cited by 62 | Viewed by 6093
Abstract
Carbon monoxide (CO) is being increasingly recognized as a potential therapeutic with important signaling functions in various diseases. Carbon monoxide-releasing molecules (CORMs) show anti-apoptotic, anti-inflammatory, and anti-oxidant effects on the tissues of organisms, thus contributing to tissue homeostasis. An increase in reactive oxygen [...] Read more.
Carbon monoxide (CO) is being increasingly recognized as a potential therapeutic with important signaling functions in various diseases. Carbon monoxide-releasing molecules (CORMs) show anti-apoptotic, anti-inflammatory, and anti-oxidant effects on the tissues of organisms, thus contributing to tissue homeostasis. An increase in reactive oxygen species production from the mitochondria after exposure to CO is also considered one of the underlying mechanisms of cardioprotection, although mitochondrial inhibition is the main toxic mechanism of CO poisoning. This review highlights the mechanism of the biological effects of CO and its potential application as a therapeutic in clinical settings, including in cardiovascular diseases. This review also discusses the obstacles and limitations of using exogenous CO or CORMs as a therapeutic option, with respect to acute CO poisoning. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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14 pages, 1339 KiB  
Review
Hydrogen Sulfide in Hypertension and Kidney Disease of Developmental Origins
by Chien-Ning Hsu and You-Lin Tain
Int. J. Mol. Sci. 2018, 19(5), 1438; https://doi.org/10.3390/ijms19051438 - 11 May 2018
Cited by 35 | Viewed by 5179
Abstract
Adverse environments occurring during kidney development may produce long-term programming effects, namely renal programming, to create increased vulnerability to the development of later-life hypertension and kidney disease. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life, even before [...] Read more.
Adverse environments occurring during kidney development may produce long-term programming effects, namely renal programming, to create increased vulnerability to the development of later-life hypertension and kidney disease. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life, even before the onset of clinical symptoms, which may counter the rising epidemic of hypertension and kidney disease. Hydrogen sulfide (H2S), the third gasotransmitter, plays a key role in blood pressure regulation and renal physiology. This review will first present the role of H2S in the renal system and provide evidence for the links between H2S signaling and the underlying mechanisms of renal programming, including the renin–angiotensin system, oxidative stress, nutrient-sensing signals, sodium transporters, and epigenetic regulation. This will be followed by potential H2S treatment modalities that may serve as reprogramming strategies to prevent hypertension and kidney disease of developmental origins. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite emerging evidence from experimental studies in support of reprogramming strategies targeting the H2S signaling pathway to protect against hypertension and kidney disease of developmental origins, these results need further clinical translation. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Gasotransmitters in Cardiovascular and Renal Disease)
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