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Introduction Control of blood flow in the microvasculature (i.e., tissue perfusion) in response to altered [0.sub.2] consumption is governed by an autoregulatory mechanism whereby flow is coupled to tissue p[O.sub.2] [...], Homeostatic control of tissue oxygenation is achieved largely through changes in blood flow that are regulated by the classic physiological response of hypoxic vasodilation. The role of nitric oxide (NO) in the control of blood flow is a central tenet of cardiovascular biology. However, extensive evidence now indicates that hypoxic vasodilation entails S-nitrosothiol--based (SNO-based) vasoactivity (ratherthan NO perse) and that this activity is conveyed substantially by the βCys93 residue in hemoglobin. Thus, tissue oxygenation in the respiratory cycle is dependent on S-nitrosohemoglobin. This perspective predicts that red blood cells (RBCs) may play an important but previously undescribed role in cardioprotection. Here, we have found that cardiac injury and mortality in models of myocardial infarction and heart failure were greatly enhanced in mice lacking βCys93 S-nitrosylation. In addition, βCys93 mutant mice exhibited adaptive collateralization of cardiac vasculature that mitigated ischemic injury and predicted outcomes after myocardial infarction. Enhanced myopathic injury and mortality across different etiologies in the absence of βCys93 confirm the central cardiovascular role of RBC-derived SNO-based vasoactivity and point to a potential locus of therapeutic intervention. Our findings also suggest the possibility that RBCs may play a previously unappreciated role in heart disease.

Two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7, are identified in an extended family with myocardial infarction; these genes encode proteins that work together to inhibit platelet activation after nitric oxide stimulation, suggesting a link between impaired nitric oxide signalling and myocardial infarction risk. Signal failure raises cardiac disease risk Next-generation sequencing in families with multiple affected individuals has revolutionized the identification of rare and private (single family or limited group) mutations. Here, the authors identify two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7, in an extended family with myocardial infarction. The products of these genes work together to induce vasodilation and inhibit platelet activation upon stimulation with nitric oxide. Starting with a severely affected family, this work identifies a link between impaired nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversal of this signalling defect may provide a new therapeutic strategy for reducing the risk of myocardial infarction. Myocardial infarction, a leading cause of death in the Western world.sup.1, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery.sup.2. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history.sup.3. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification.sup.4. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the [alpha]1 subunit of soluble guanylyl cyclase ([alpha]1-sGC).sup.5, and CCT7 encodes CCT[eta], a member of the tailless complex polypeptide 1 ring complex.sup.6, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation.sup.7. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce [alpha]1-sGC as well as [beta]1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in [alpha]1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction., Author(s): Jeanette Erdmann [sup.1] [sup.2] , Klaus Stark [sup.3] [sup.4] , Ulrike B. Esslinger [sup.3] [sup.5] , Philipp Moritz Rumpf [sup.6] [sup.7] , Doris Koesling [sup.8] , Cor de Wit [...]

Introduction After acute myocardial infarction, timely and successful reperfusion is the most effective strategy for reducing the infarct size and improving the clinical outcome. However, blood restoration by reperfusion of [...], This study used a model of ischemia-reperfusion injury to the brachial artery endothelium to investigate whether the protective role of ischemic postconditioning (IPostC) is impaired in patients with major depressive episode. Flow-mediated dilation (FMD) was measured before and after ischemia-reperfusion in the absence or presence of IPostC in 24 patients with major depressive disorder and 20 healthy controls. In addition, the severity of the depression, as assessed by the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores, and plasma nitrogen dioxide (N[O.sub.x]) levels were also determined. Ischemia-reperfusion resulted in a significant decrease in FMD in both patients with a major depressive episode and healthy controls. IPostC effectively prevented this decrease in FMD in healthy controls, but not in patients with a major depressive episode. HDRS and BDI scores were markedly increased, but plasma N[O.sub.x] levels decreased, in patients with a major depressive episode compared with those in healthy controls. Correlation analysis showed that HDRS and BDI scores and plasma NOx levels were significantly associated with post-ischemiareperfusion FMD. These results suggest that endothelial protection by IPostC is impaired in patients with major depressive disorder, which may be related to the decrease in endothelial nitric oxide production and the severity of the depression. Key words: ischemic postconditioning, ischemia-reperfusion, major depressive disorder, nitric oxide. Resume : Un modele d'ischemie-reperfusion de l'endothelium de l'artere brachiale a ete utilise afin de determiner si le role protecteur d'un post-conditionnement ischemique (PostCI) est affaibli chez les patients qui presentent un episode de depression majeure. La dilatation induite par le flux (DIF) a ete mesuree avant et apres l' ischemie-reperfusion en absence ou en presence de PostCI chez 24 patients atteints de depression majeure et 20 individus sains. De plus, la severite de la depression a ete evaluee par l'Echelle de depression de Hamilton (EDH) et par l'Inventaire de depression de Beck (IDB), et le niveau de dioxydes d'azote (N[O.sub.x]) plasmatiques a aussi ete determine. L'ischemie-reperfusion a resulte en une diminution significative de la DIF chez les patients presentant un episode de depression majeure et les individus controles sains. Le PostCI a prevenu efficacement cette diminution de la DIF chez les individus sains, mais pas chez les patients presentant un episode de depression majeure. Les scores de EDH et de IDB etaient fortement augmentes chez les patients presentant un episode de depression majeure, mais les niveaux plasmatiques de NOx etaient diminues comparativement aux controles sains. L' analyse de correlation a montre que les scores de EDH et de IDB et les niveaux plasmatiques de N[O.sub.x] etaient significativement associes a la DIF post-ischemie-reperfusion. Ces resultats suggerent que la protection endotheliale conferee par le PostCI est affaiblie chez les patients presentant un episode de depression majeure, ce qui pourrait etre relie a la diminution de la production de nitric oxide endothelial et a la severite de la depression. Mots-cles: post-conditionnement ischemique, ischemie-reperfusion, depression majeure, oxyde nitrique. [Traduit par la Redaction]

Introduction The Rho/Rac GTPase family is composed of a large number of members that, according to structural similarity criteria, are subclassified into Rho, Rac, and Cdc42 subfamilies (1). Upon activation, [...], The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide-triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.

Abstract Nine rotenoids were isolated from the hexane and dichloromethane extracts ofDerris trifoliata stems and were tested for nitric oxide (NO) inhibitory activity using RAW264.7 cells. The result indicated that [...]

Abstract: Cadmium (Cd) perturbs vascular health and interferes with endothelial function. However, the effects of exposing endothelial cells to low doses of Cd on the production of nitric oxide (NO) [...]

Objective: To examine possible adverse effects on haemostasis from prolonged exposure to inhaled nitric oxide (iNO). Design and setting: Blinded, randomised, experimental animal study in a university animal laboratory. Interventions: Anaesthetised and intubated piglets received central venous, arterial, and transabdominal urinary catheters. Twelve piglets were studied with triggered pressure support ventilation breathing with an air-oxygen mixture for 30 h with nitric oxide (NO), 40 parts per million (ppm) (n = 6) or without NO gas (n = 6) added. The tests of platelet function were assessed in a separate 1-h experiment in which 12 additional animals were blindly randomised to receive intravenous acetylsalicylic acid (ASA) (n = 7) or placebo (n = 5). Measurements and results: All 12 animals were clinically stable during the study period of 30 h. Haemostasis was assessed in terms of bleeding time and platelet function by Adeplat-S, reflecting platelet adhesion. Prothrombin fragment 1 + 2, fibrin D-dimer, tissue plasminogen activator and prothrombin complex were measured to investigate whether inhaled NO (iNO) had any effects on thrombin formation, fibrin formation, fibrinolysis or coagulation. All parameters including bleeding time and Adeplat-S were unaffected by iNO. ASA significantly increased bleeding time, but did not affect Adeplat-S. Nitrate in plasma and NOx (nitrate and nitrite) in urine increased significantly in pigs receiving iNO compared with controls. Conclusions: Prolonged exposure to iNO at 40 ppm did not affect bleeding time or coagulation parameters in healthy piglets. The findings do not support the hypothesis that iNO increases the risk of bleeding in humans. Keywords Inhalation * Nitric oxide * Haemostasis * Bleeding time * Adverse effects * Platelets, Introduction Inhaled nitric oxide (iNO) has been used since 1992 as a selective pulmonary vasodilator [1, 2] and is registered for use in newborns with severe hypoxic respiratory failure [3]. [...]

HMR1766 is a new nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients [...]

The field of NO has grown immensely from the incredulous proposal as a biological molecule to a field with 80,000 publications and touching all aspects of physiology and pathology. Inhaled [...]

A. Nitric Oxide and Peroxynitrite in Cardiac Diseases Calcium-dependent NOSs are responsible for the generation of NO in cardiomyocytes, endocardial endothelium, coronary endothelium, and cardiac nerves. NO serves many important [...]

I. Introduction II. Nitric Oxide A. Discovery of nitric oxide as a biological molecule B. The selective reactivity of nitric oxide C. Diffusion and signaling properties of nitric oxide D. [...]

Abstract: This study investigates mechanisms underlying [β.sub.3]-adrenergic activation of the endothelial nitric oxide synthase (eNOS) in myocardial tissue of wildtype (WT) and [β.sub.3]-adrenoceptor knockout ([β.sub.3]-KNO) mice, in the absence and [...]