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Thoonen, Robrecht

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Thoonen

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Robrecht

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Thoonen, Robrecht
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Now showing 1 - 7 of 7
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    Pathophysiology of Hypertension in the Absence of Nitric Oxide/Cyclic GMP Signaling
    (Springer Science + Business Media, 2012) Thoonen, Robrecht; Sips, Patrick; Bloch, Kenneth; Buys, Emmanuel
    The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling system is a well-characterized modulator of cardiovascular function, in general, and blood pressure, in particular. The availability of mice mutant for key enzymes in the NO-cGMP signaling system facilitated the identification of interactions with other blood pressure modifying pathways (e.g. the renin-angiotensin-aldosterone system) and of gender-specific effects of impaired NO-cGMP signaling. In addition, recent genome-wide association studies identified blood pressure-modifying genetic variants in genes that modulate NO and cGMP levels. Together, these findings have advanced our understanding of how NO-cGMP signaling regulates blood pressure. In this review, we will summarize the results obtained in mice with disrupted NO-cGMP signaling and highlight the relevance of this pathway as a potential therapeutic target for the treatment of hypertension.
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    Heme deficiency of soluble guanylate cyclase induces gastroparesis
    (Wiley-Blackwell, 2013) Cosyns, S. M. R.; Dhaese, I.; Thoonen, Robrecht; Buys, Emmanuel; Vral, A.; Brouckaert, P.; Lefebvre, R. A.
    Background: Soluble guanylate cyclase (sGC) is the principal target of nitric oxide (NO) to control gastrointestinal motility. The consequence on nitrergic signaling and gut motility of inducing a heme-free status of sGC, as induced by oxidative stress, was investigated. Methods: sGCβ1H105F knock-in (apo-sGC) mice, which express heme-free sGC that has basal activity, but cannot be stimulated by NO, were generated. Key Results: Diethylenetriamine NONOate did not increase sGC activity in gastrointestinal tissue of apo-sGC mice. Exogenous NO did not induce relaxation in fundic, jejunal and colonic strips, and pyloric rings of apo-sGC mice. The stomach was enlarged in apo-sGC mice with hypertrophy of the muscularis externa of the fundus and pylorus. In addition, gastric emptying and intestinal transit were delayed and whole-gut transit time was increased in the apo-sGC mice, while distal colonic transit time was maintained. The nitrergic relaxant responses to electrical field stimulation at 1–4 Hz were abolished in fundic and jejunal strips from apo-sGC mice, but in pyloric rings and colonic strips, only the response at 1 Hz was abolished, indicating the contribution of other transmitters than NO. Conclusions & Inferences: The results indicate that the gastrointestinal consequences of switching from a native sGC to a heme-free sGC, which cannot be stimulated by NO, are most pronounced at the level of the stomach establishing a pivotal role of the activation of sGC by NO in normal gastric functioning. In addition, delayed intestinal transit was observed, indicating that nitrergic activation of sGC also plays a role in the lower gastrointestinal tract.
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    Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy
    (Elsevier BV, 2015) Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Chen, Chan; Chao, Wei; Panagia, Marcello; Sosnovik, David; Puppala, Dheeraj; Armoundas, Antonis; Hindle, Allyson; Bloch, Kenneth; Buys, Emmanuel; Scherrer-Crosbie, Marielle
    Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1−/−) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1−/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1−/− mice. UCP1−/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1−/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1−/− BAT transplanted to either UCP1−/− or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1−/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1−/− mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy.
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    Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice
    (Springer Nature, 2015) Thoonen, Robrecht; Cauwels, Anje; Decaluwe, Kelly; Geschka, Sandra; Tainsh, Robert; Delanghe, Joris; Hochepied, Tino; De Cauwer, Lode; Rogge, Elke; Voet, Sofie; Sips, Patrick; Karas, Richard H.; Bloch, Kenneth; Vuylsteke, Marnik; Stasch, Johannes-Peter; Van de Voorde, Johan; Buys, Emmanuel; Brouckaert, Peter
    Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.
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    In vitro and in vivo studies on the importance of the soluble guanylyl cyclase a1 subunit in penile erection
    (Springer Nature, 2010) Decaluwé, Kelly; Nimmegeers, Sofie; Thoonen, Robrecht; Buys, Emmanuel; Brouckaert, Peter; Van de Voorde, Johan
    Purpose: Soluble guanylyl cyclase (sGC), which plays a pivotal role in penile erection, is a heterodimer build up by an α and a β subunit. For both subunits two isoforms have been characterized, but only the sGCα1β1 and sGCα2β1 isoforms seem to be functionally active. To elucidate the functional role of the sGCα1β1 heterodimer in the mechanism of erection, experiments were performed in vivo and on isolated corpora cavernosa (CC) using sGCα1−/− mice. Materials and methods: For the in vivo study sGC-dependent and -independent vasorelaxing agents were injected intracavernosally in sGCα1−/− and sGCα1+/+ mice and the rise in intracavernosal pressure was recorded. For the in vitro study, isolated CC tissues from sGCα1−/− and sGCα1+/+ mice were mounted in organ baths for isometric tension recording and concentration-dependent curves were obtained for sGC-dependent and -independent vasorelaxing agents. These experiments were performed on 2 different mice strains (129SvEvS7 and C57BL6/J) to determine potential strain differences. Results: The responses in sGCα1−/− after administration of the NO-donors, sodium nitroprusside (SNP) and spermine-NO, and to electrical stimulation are significantly reduced although not completely abolished. Responses to sGC-independent vasorelaxing agents are similar in sGCα1−/− and sGCα1+/+ mice from both strains suggesting that the decreased potential of smooth muscle relaxation is not related to structural changes or changes in the pathway downstream sGC. Conclusion: This study illustrates the strain-independent importance of the sGCα1β1 heterodimer, although remaining vasorelaxing responses in the sGCα1−/− mice suggest a complementary role for the sGCα2β1 isoform or (an) sGC-independent mechanism(s).
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    Erectile Dysfunction in Heme-Deficient Nitric Oxide–Unresponsive Soluble Guanylate Cyclase Knock-In Mice
    (Elsevier BV, 2017) Decaluwé, Kelly; Pauwels, Bart; Boydens, Charlotte; Thoonen, Robrecht; Buys, Emmanuel; Brouckaert, Peter; Van de Voorde, Johan
    Introduction: The nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) pathway is the leading pathway in penile erection. Aim: To assess erectile function in a mouse model in which sGC is deficient in heme (apo-sGC) and unresponsive to NO. Methods: Mutant mice (sGCb1 ki/ki) that express an sGC enzyme that retains basal activity but fails to respond to NO because of heme deficiency (apo-sGC) were used. Isolated corpora cavernosa from sGCb1 ki/ki and wild-type mice were mounted in vitro for isometric tension recordings in response to sGC-dependent and -independent vasorelaxant agents. In addition, the erectile effects of some of these agents were tested in vivo at intracavernosal injection. Main Outcome Measures: In vitro and in vivo recordings of erectile responses in sGCb1 ki/ki and wild-type mice after stimulation with sGC-dependent and -independent vasorelaxant agents. Results: NO-induced responses were abolished in sGCb1 ki/ki mice in vitro and in vivo. The ability of the heme-dependent, NO-independent sGC stimulator BAY 41-2272 to relax the corpora cavernosa was markedly attenuated in sGCb1 ki/ki mice. In contrast, the relaxation response to the heme- and NO-independent sGC activator BAY 58-2667 was significantly enhanced in sGCb1 ki/ki mice. The relaxing effect of sGC-independent vasorelaxant agents was similar in wild-type and sGCb1 ki/ki mice, illustrating that the observed alterations in vasorelaxation are limited to NO-sGC-cGMPemediated processes. Conclusion: Our results suggest that sGC is the sole target of NO in erectile physiology. Furthermore, this study provides indirect evidence that, in addition to sGCa1b1, sGCa2b1 is important for erectile function. In addition, the significant relaxation observed in sGCb1 ki/ki mice with the cumulative addition of the sGC activator BAY 58-2667 indicates that sGC activators might offer value in treating erectile dysfunction.
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    Androgen-sensitive hypertension associated with soluble guanylate cyclase alpha1 deficiency is mediated by 20-HETE
    (BioMed Central, 2015) Vandenwijngaert, Sara; Dordea, Ana C; Garcia, Victor; Tainsh, Robert E; Nathan, Daniel I; Raher, Michael J; Allen, Kaitlin; Zhang, Fan; Lieb, Wolfgang S; Mikelman, Sarah; Kirby, Andrew; Stevens, Christine; Thoonen, Robrecht; Hindle, Allyson; Sips, Patrick Y; Malhotra, Rajeev; Daly, Mark; Brouckaert, Peter; Bloch, Kenneth D; Schwartzman, Michal; Buys, Emmanuel