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Special Issue "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 "Bioinorganic Chemistry".

Deadline for manuscript submissions: 21 December 2018

Special Issue Editors

Guest Editor
Prof. Dr. Jaap A. Joles

Department of Nephrology and Hypertension, Laboratory of Renal and Vascular Biology, University Medical Center Utrecht, Utrecht, The Netherlands
Website | E-Mail
Interests: cardiorenal and renocardiac syndrome; pre-eclampsia and fetal growth retardation; developmental plasticity in relation to hypertension and renal disease; metabolic syndrome and type 2 diabetes; renal hypoxia
Guest Editor
Prof. Dr. Harry van Goor

Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Website | E-Mail

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

Manuscript Submission Information

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Keywords

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

Published Papers (6 papers)

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Research

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Open AccessArticle Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide
Int. J. Mol. Sci. 2018, 19(10), 3248; https://doi.org/10.3390/ijms19103248
Received: 14 September 2018 / Revised: 30 September 2018 / Accepted: 10 October 2018 / Published: 19 October 2018
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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
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Open AccessArticle Exercise Training Has Contrasting Effects in Myocardial Infarction and Pressure Overload Due to Divergent Endothelial Nitric Oxide Synthase Regulation
Int. J. Mol. Sci. 2018, 19(7), 1968; https://doi.org/10.3390/ijms19071968
Received: 18 May 2018 / Revised: 19 June 2018 / Accepted: 28 June 2018 / Published: 6 July 2018
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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
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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
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Review

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Open AccessReview Role of Nitric Oxide in the Cardiovascular and Renal Systems
Int. J. Mol. Sci. 2018, 19(9), 2605; https://doi.org/10.3390/ijms19092605
Received: 22 July 2018 / Revised: 30 August 2018 / Accepted: 31 August 2018 / Published: 3 September 2018
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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
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Open AccessReview The Role of Midkine in Arteriogenesis, Involving Mechanosensing, Endothelial Cell Proliferation, and Vasodilation
Int. J. Mol. Sci. 2018, 19(9), 2559; https://doi.org/10.3390/ijms19092559
Received: 23 July 2018 / Revised: 17 August 2018 / Accepted: 22 August 2018 / Published: 29 August 2018
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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
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Open AccessReview Therapeutic Aspects of Carbon Monoxide in Cardiovascular Disease
Int. J. Mol. Sci. 2018, 19(8), 2381; https://doi.org/10.3390/ijms19082381
Received: 19 July 2018 / Revised: 8 August 2018 / Accepted: 8 August 2018 / Published: 13 August 2018
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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
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Open AccessReview Hydrogen Sulfide in Hypertension and Kidney Disease of Developmental Origins
Int. J. Mol. Sci. 2018, 19(5), 1438; https://doi.org/10.3390/ijms19051438
Received: 12 April 2018 / Revised: 1 May 2018 / Accepted: 9 May 2018 / Published: 11 May 2018
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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
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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
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