scispace - formally typeset
Search or ask a question
Author

Patrick Sips

Bio: Patrick Sips is an academic researcher from Ghent University. The author has contributed to research in topics: Nitric oxide & Soluble guanylyl cyclase. The author has an hindex of 19, co-authored 62 publications receiving 1334 citations. Previous affiliations of Patrick Sips include Brigham and Women's Hospital & Flanders Institute for Biotechnology.


Papers
More filters
Journal ArticleDOI
TL;DR: It is suggested that administration of Na2S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3–dependent signaling pathway.
Abstract: Background— Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H2S) on the outcome after CA and cardiopulmonary resuscitation (CPR) in mouse. Methods and Results— Mice were subjected to 8 minutes of normothermic CA and resuscitated with chest compression and mechanical ventilation. Seven minutes after the onset of CA (1 minute before CPR), mice received sodium sulfide (Na2S) (0.55 mg/kg IV) or vehicle 1 minute before CPR. There was no difference in the rate of return of spontaneous circulation, CPR time to return of spontaneous circulation, and left ventricular function at return of spontaneous circulation between groups. Administration of Na2S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na2S). Administration of Na2S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delaye...

184 citations

Journal ArticleDOI
TL;DR: The data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eN OS and/or PI3K or Akt as new potential targets for treating anaphlyaxis.
Abstract: Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCα1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis.

130 citations

Journal ArticleDOI
TL;DR: It is demonstrated that sGCalpha1beta1-derived cGMP signalling has gender-specific and testosterone-dependent cardiovascular effects and reveal that the effects of NO on systemic blood pressure do not require sG Calpha1 beta1.
Abstract: Aim The effects of nitric oxide (NO) in the cardiovascular system are attributed in part to cGMP synthesis by the α1β1 isoform of soluble guanylate cyclase (sGC). Because available sGC inhibitors are neither enzyme- nor isoform-specific, we generated knockout mice for the α1 subunit (sGCα1−/− mice) in order to investigate the function of sGCα1β1 in the regulation of blood pressure and cardiac function. Methods and results Blood pressure was evaluated, using both non-invasive and invasive haemodynamic techniques, in intact and gonadectomized male and female sGCα1−/− and wild-type (WT) mice. Cardiac function was assessed with a conductance catheter inserted in the left ventricle of male and female sGCα1−/− and WT mice. Male sGCα1−/− mice developed hypertension (147 ± 2 mmHg), whereas female sGCα1−/− mice did not (115 ± 2 mmHg). Orchidectomy and treatment with an androgen receptor antagonist prevented hypertension, while ovariectomy did not influence the phenotype. Chronic testosterone treatment increased blood pressure in ovariectomized sGCα1−/− mice but not in WT mice. The NO synthase inhibitor N ω -nitro-L-arginine methyl ester hydrochloride raised blood pressure similarly in male and female WT and sGCα1−/− mice. The ability of NO donor compounds to reduce blood pressure was slightly attenuated in sGCα1−/− male and female mice as compared to WT mice. The direct sGC stimulator BAY 41-2272 reduced blood pressure only in WT mice. Increased cardiac contractility and arterial elastance as well as impaired ventricular relaxation were observed in both male and female sGCα1−/− mice. Conclusion These findings demonstrate that sGCα1β1-derived cGMP signalling has gender-specific and testosterone-dependent cardiovascular effects and reveal that the effects of NO on systemic blood pressure do not require sGCα1β1.

113 citations

Journal ArticleDOI
TL;DR: NO inhalation after CA and successful CPR improves outcome via soluble guanylate cyclase–dependent mechanisms, and the protective effects of inhaled NO on the outcome after CA/CPR were associated with reduced water diffusion abnormality, caspase-3 activation and cytokine induction in the brain and increased serum nitrate/nitrite levels.
Abstract: Background—Sudden cardiac arrest (CA) is a leading cause of death worldwide. Breathing nitric oxide (NO) reduces ischemia/reperfusion injury in animal models and in patients. The objective of this study was to learn whether inhaled NO improves outcomes after CA and cardiopulmonary resuscitation (CPR). Methods and Results—Adult male mice were subjected to potassium-induced CA for 7.5 minutes whereupon CPR was performed with chest compression and mechanical ventilation. One hour after CPR, mice were extubated and breathed air alone or air supplemented with 40 ppm NO for 23 hours. Mice that were subjected to CA/CPR and breathed air exhibited a poor 10-day survival rate (4 of 13), depressed neurological and left ventricular function, and increased caspase-3 activation and inflammatory cytokine induction in the brain. Magnetic resonance imaging revealed brain regions with marked water diffusion abnormality 24 hours after CA/CPR in mice that breathed air. Breathing air supplemented with NO for 23 hours starting...

94 citations

Journal ArticleDOI
TL;DR: The future potential of zebrafish as a tool to further dissect the molecular basis of phenotypic variability in human type I collagenopathies is illustrated to improve diagnostic strategies as well as promote the discovery of new targetable pathways for pharmacological intervention of these disorders.
Abstract: The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of osteogenesis imperfecta (OI) and the Ehlers–Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and a zebrafish model resembling human EDS, which harbors a number of soft connective tissues defects, typical of EDS. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen-related disease models. Our studies reveal a high degree of intergenotype variability in phenotypic expressivity that closely correlates with associated OI severity. Furthermore, we demonstrate the potential for select mutations to give rise to phenotypic variability, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the future potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention.

77 citations


Cited by
More filters
Journal ArticleDOI
Rui Wang1
TL;DR: The important life-supporting role of hydrogen sulfide (H(2)S) has evolved from bacteria to plants, invertebrates, vertebrate, vertebrates, and finally to mammals, but over the centuries it had only been known for its toxicity and environmental hazard.
Abstract: The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

1,560 citations

Journal ArticleDOI
TL;DR: The results of the current study show that H2S and NO are mutually required to elicit angiogenesis and vasodilatation, and the cooperative action of the two gasotransmitters on increasing and maintaining intracellular cGMP is essential for PKG activation and angiogenic and vasorelaxation.
Abstract: Hydrogen sulfide (H2S) is a unique gasotransmitter, with regulatory roles in the cardiovascular, nervous, and immune systems. Some of the vascular actions of H2S (stimulation of angiogenesis, relaxation of vascular smooth muscle) resemble those of nitric oxide (NO). Although it was generally assumed that H2S and NO exert their effects via separate pathways, the results of the current study show that H2S and NO are mutually required to elicit angiogenesis and vasodilatation. Exposure of endothelial cells to H2S increases intracellular cyclic guanosine 5′-monophosphate (cGMP) in a NO-dependent manner, and activated protein kinase G (PKG) and its downstream effector, the vasodilator-stimulated phosphoprotein (VASP). Inhibition of endothelial isoform of NO synthase (eNOS) or PKG-I abolishes the H2S-stimulated angiogenic response, and attenuated H2S-stimulated vasorelaxation, demonstrating the requirement of NO in vascular H2S signaling. Conversely, silencing of the H2S-producing enzyme cystathionine-γ-lyase abolishes NO-stimulated cGMP accumulation and angiogenesis and attenuates the acetylcholine-induced vasorelaxation, indicating a partial requirement of H2S in the vascular activity of NO. The actions of H2S and NO converge at cGMP; though H2S does not directly activate soluble guanylyl cyclase, it maintains a tonic inhibitory effect on PDE5, thereby delaying the degradation of cGMP. H2S also activates PI3K/Akt, and increases eNOS phosphorylation at its activating site S1177. The cooperative action of the two gasotransmitters on increasing and maintaining intracellular cGMP is essential for PKG activation and angiogenesis and vasorelaxation. H2S-induced wound healing and microvessel growth in matrigel plugs is suppressed by pharmacological inhibition or genetic ablation of eNOS. Thus, NO and H2S are mutually required for the physiological control of vascular function.

555 citations

Journal ArticleDOI
01 Aug 2006-BMJ

522 citations

Journal ArticleDOI
TL;DR: Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide (NO) signaling pathway, is attracting rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists currently in clinical development.
Abstract: Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide (NO) signaling pathway, is attracting rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists currently in clinical development. On binding of NO to a prosthetic heme group on sGC, the enzyme catalyzes synthesis of the second messenger cGMP, which produces vasorelaxation and inhibits smooth muscle proliferation, leukocyte recruitment, and platelet aggregation through a number of downstream mechanisms.1,2 Impaired NO and cGMP signaling has been implicated in the pathogenesis of cardiovascular disease, including systemic arterial and pulmonary hypertension (PH), coronary artery disease, peripheral vascular disease (including erectile dysfunction), and atherosclerosis.1,3,–,5 Organic nitrates that target the NO signaling pathway have been used to treat cardiovascular disease for >150 years. More recently, gaseous NO administered by inhalation has been approved for the treatment of persistent PH of the newborn.3,6 These agents nonetheless have several important limitations. Cardiovascular disease is associated with resistance to NO and organic nitrates.7 This may be due to the oxidative stress–induced alteration of the redox state of the prosthetic heme on sGC (from ferrous to ferric) that weakens the binding of heme to the enzyme and renders sGC unresponsive to NO.1,8 Furthermore, the long-term efficacy of organic nitrates is limited by the development of tolerance.9 Nitric oxide may also have numerous cytotoxic effects, mostly attributed to the reactive oxidant peroxynitrite (formed from the diffusion-controlled reaction of NO with superoxide).3,10 Peroxynitrite interacts with proteins and lipids, altering cellular signaling, disrupting mitochondrial function, and damaging DNA, which can eventually culminate in cellular dysfunction and/or death.3 Because the beneficial effects of NO appear to be …

508 citations

14 Jan 2013
TL;DR: In this paper, the authors describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated Zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis.
Abstract: Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

503 citations