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1.
Artigo em Inglês | MEDLINE | ID: mdl-31743994

RESUMO

In the microcirculation, the exchange of nutrients, water, gas, hormones, and waste takes place, and it is divided into the three main sections arterioles, capillaries, and venules. Disturbances in the microcirculation can be measured using surrogate parameters or be visualized either indirectly or directly.Arginase is a manganese metalloenzyme hydrolyzing L-arginine to urea and L-ornithine. It is located in different cell types, including vascular cells, but also in circulating cells such as red blood cells. A variety of pro-inflammatory factors, as well as interleukins, stimulate increased arginase expression. An increase in arginase activity consequently leads to a consumption of L-arginine needed for nitric oxide (NO) production by endothelial NO synthase. A vast body of evidence convincingly showed that increased arginase activity is associated with endothelial dysfunction in larger vessels of the vascular tree. Of note, arginase also influences the microcirculation. Arginase inhibition leads to an increase in the bioavailability of NO and reduces superoxide levels, resulting in improved endothelial function. Arginase inhibition might, therefore, be a potent treatment strategy in cardiovascular medicine. Recently, red blood cells emerged as an influential player in the development from increased arginase activity to endothelial dysfunction. As red blood cells directly interact with the microcirculation in gas exchange, this could constitute a potential link between arginase activity, endothelial dysfunction and microcirculatory disturbances.The aim of this review is to summarize recent findings revealing the role of arginase in regulating vascular function with particular emphasis on the microcirculation.

2.
Atherosclerosis ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606133

RESUMO

BACKGROUND AND AIMS: Endothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages. METHODS: Carotid plaques and blood samples were retreived from patients undergoing surgery for symptomatic or asymptomatic carotid stenosis. Plaque gene and protein expression was determined and related to clinical characteristics. Functional interactions between ET-1 and arginase were investigated in endothelial cells and THP-1 cells. RESULTS: Expression of ET-1 and ETB receptors was increased in plaques from patients with symptomatic carotid artery disease. ET-1 was co-localized with arginase 1 and arginase 2 in the necrotic core, together with macrophage markers CD163 and CD68. Arginase 2, ET-1 and ETB receptors were expressed in endothelial cells as well as in smooth muscle cells in the fibrous cap. ET-1 increased arginase 2 mRNA expression and arginase activity in endothelial cells and arginase activity in macrophages. Moreover, ET-1 stimulated formation of reactive oxygen species (ROS) in THP-1-derived macrophages via an arginase-dependent mechanism. CONCLUSIONS: This is the first study that demonstrates co-localization of ET-1 and arginase 2 in human atherosclerotic plaques. ET-1 stimulated arginase 2 expression and activity in endothelial cells, as well as arginase activity and ROS formation in macrophages via an arginase-dependent mechanism. These results indicate an important interaction between the ET pathway and arginase in human atherosclerotic plaques.

3.
J Cardiovasc Pharmacol Ther ; : 1074248419874348, 2019 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-31495204

RESUMO

INTRODUCTION: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Cellular interactions of red blood cells (RBCs) and platelets with endothelial cells and cardiomyocytes play a crucial role in cardiac ischemia/reperfusion (I/R) injury. However, addressing the specific impact of such cell-to-cell interactions in commonly employed in vivo models of cardiac I/R injury is challenging due to overlap of neuronal, hormonal, and immunological pathways. This study aimed to refine a Langendorff-based ex vivo transfer model to evaluate the impact of specific blood components on cardiac I/R injury. MATERIAL AND METHODS: Murine whole blood, defined murine blood components (RBCs, platelet-rich plasma [PRP], and platelet-poor plasma [PPP], respectively) as well as human RBCs were loaded to the coronary system of isolated murine hearts in a Langendorff system before initiating global ischemia for 40 minutes. Following 60 minutes of reperfusion with Krebs Henseleit Buffer, left ventricular function and coronary flow were assessed. Infarct size was determined by specific histological staining following 120 minutes of reperfusion. RESULTS: Loading of murine whole blood to the coronary system of isolated murine hearts at the beginning of 40 minutes of global ischemia improved left ventricular function after 60 minutes of reperfusion and reduced the infarct size in comparison to buffer-treated controls. Similarly, isolated murine RBCs, PRP, and PPP mediated a protective effect in the cardiac I/R model. Furthermore, human RBCs showed a comparable protective capacity as murine RBCs. CONCLUSION: This Langendorff-based transfer model of cardiac I/R injury is a feasible, time-, and cost-effective model to evaluate the impact of blood components on myocardial infarction. The presented method facilitates loading of blood components of genetically modified mice to murine hearts of a different mouse strain, thus complementing time- and cost-intensive chimeric models and contributing to the development of novel targeted therapies.

4.
Cardiovasc Res ; 115(11): 1596-1605, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31198931

RESUMO

The primary role of red blood cells (RBCs) is to transport oxygen to the tissues and carbon dioxide to the lungs. However, emerging evidence suggests an important role of the RBC beyond being just a passive carrier of the respiratory gases. The RBCs are of importance for redox balance and are actively involved in the regulation of vascular tone, especially during hypoxic and ischaemic conditions by the release of nitric oxide (NO) bioactivity and adenosine triphosphate. The role of the RBC has gained further interest after recent discoveries demonstrating a markedly altered function of the cell in several pathological conditions. Such alterations include increased adhesion capability, increased formation of reactive oxygen species as well as altered protein content and enzymatic activities. Beyond signalling increased oxidative stress, the altered function of RBCs is characterized by reduced export of NO bioactivity regulated by increased arginase activity. Of further importance, the altered function of RBCs has important implications for several cardiovascular disease conditions. RBCs have been shown to induce endothelial dysfunction and to increase cardiac injury during ischaemia-reperfusion in diabetes mellitus. Finally, this new knowledge has led to novel therapeutic possibilities to intervene against cardiovascular disease by targeting signalling in the RBC. These novel data open up an entirely new view on the underlying pathophysiological mechanisms behind the cardiovascular disease processes in diabetes mellitus mediated by the RBC. This review highlights the current knowledge regarding the role of RBCs in cardiovascular regulation with focus on their importance for cardiovascular dysfunction in pathological conditions and therapeutic possibilities for targeting RBCs in cardiovascular disease.

5.
Eur Heart J Acute Cardiovasc Care ; : 2048872619848978, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31081342

RESUMO

BACKGROUND: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial did not find any benefit of oxygen therapy compared to ambient air in normoxemic patients with suspected acute myocardial infarction. Patients with chronic obstructive pulmonary disease may both benefit and be harmed by supplemental oxygen. Thus we evaluated the effect of routine oxygen therapy compared to ambient air in normoxemic chronic obstructive pulmonary disease patients with suspected acute myocardial infarction. METHODS AND RESULTS: A total of 6629 patients with suspected acute myocardial infarction were randomly assigned in the DETO2X-AMI trial to oxygen or ambient air. In the oxygen group ( n=3311) and the ambient air group ( n=3318), 155 and 141 patients, respectively, had chronic obstructive pulmonary disease (prevalence of 4.5%). Patients with chronic obstructive pulmonary disease were older, had more comorbid conditions and experienced a twofold higher risk of death at one year (chronic obstructive pulmonary disease: 32/296 (10.8%) vs. non-chronic obstructive pulmonary disease: 302/6333 (4.8%)). Oxygen therapy compared to ambient air was not associated with improved outcomes at 365 days (chronic obstructive pulmonary disease: all-cause mortality hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.50-1.99, Pinteraction=0.96); cardiovascular death HR 0.80, 95% CI 0.32-2.04, Pinteraction=0.59); rehospitalisation with acute myocardial infarction or death HR 1.27, 95% CI 0.71-2.28, Pinteraction=0.46); hospitalisation for heart failure or death HR 1.08, 95% CI 0.61-1.91, Pinteraction=0.77]); there were no significant treatment-by-chronic obstructive pulmonary disease interactions. CONCLUSIONS: Although chronic obstructive pulmonary disease patients had twice the mortality rate compared to non-chronic obstructive pulmonary disease patients, this prespecified subgroup analysis from the DETO2X-AMI trial on oxygen therapy versus ambient air in normoxemic chronic obstructive pulmonary disease patients with suspected acute myocardial infarction revealed no evidence for benefit of routine oxygen therapy consistent with the main trial's findings. CLINICAL TRIALS REGISTRATION: NCT02290080.

6.
Circulation ; 139(23): 2654-2663, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905171

RESUMO

BACKGROUND: Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin ß chain (ß93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection. METHODS: To test this hypothesis, we used RBCs from mice in which the ß93 cysteine had been replaced with alanine (ß93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity. RESULTS: In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (ß93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with ß93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in ß93C and ß93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between ß93C and ß93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in ß93C and ß93A mice. CONCLUSIONS: RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the ß93 cysteine of Hb.

7.
Int J Cardiol ; 274: 40-44, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30268384

RESUMO

BACKGROUND: Remote ischemic conditioning (RIC), i.e. short cycles of ischemia and reperfusion in remote tissue, is a novel approach to protect against myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction. The nature of the factors transmitting the protective effect of RIC remains unknown, and both neuronal and hormonal mechanisms appear to be involved. A recent study indicated involvement of glucagon-like peptide-1 (GLP-1) regulated by the vagal nerve in RIC in rats. In the present study we aimed to investigate whether the protective effect of RIC is mediated by a GLP-1 receptor-dependent mechanism in humans. METHODS: Endothelial function was determined from flow-mediated dilatation (FMD) of the brachial artery before and after 20 min of forearm ischemia and 20 min of reperfusion in twelve healthy subjects on three occasions: (A) ischemia-reperfusion without intervention, (B) ischemia-reperfusion + RIC and (C) iv administration of the GLP-1 receptor antagonist exendin(9-39) + ischemia-reperfusion + RIC. RESULTS: Ischemia-reperfusion reduced FMD from 4.7 ±â€¯0.8% at baseline to 1.5 ±â€¯0.4% (p < 0.01). RIC protected from the impairment in FMD induced by ischemia-reperfusion (4.6 ±â€¯1.1% at baseline vs. 5.0 ±â€¯1.1% following ischemia-reperfusion). Exendin(9-39) abolished the protection induced by RIC (FMD 4.9 ±â€¯0.9% at baseline vs. 1.4 ±â€¯1.3% following ischemia-reperfusion; p < 0.01) but did not affect basal FMD. Plasma GLP-1 levels did not change significantly between examinations. CONCLUSION: The present study is the first to suggest that RIC protects against endothelial ischemia-reperfusion injury via a GLP-1 receptor-mediated mechanism in humans.


Assuntos
Endotélio Vascular/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Vasodilatação/fisiologia , Adulto , Artéria Braquial/fisiopatologia , Endotélio Vascular/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia
8.
Cardiovasc Res ; 115(7): 1156-1166, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590395

RESUMO

During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

9.
Pharmacol Res ; 141: 32-45, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30553823

RESUMO

Uridine adenosine tetraphosphate (Up4A), biosynthesized by activation of vascular endothelial growth factor receptor (VEGFR) 2, was initially identified as a potent endothelium-derived vasoconstrictor in perfused rat kidney. Subsequently, the effect of Up4A on vascular tone regulation was intensively investigated in arteries isolated from different vascular beds in rodents including rat pulmonary arteries, aortas, mesenteric and renal arteries as well as mouse aortas, in which Up4A produces vascular contraction. In contrast, Up4A produces vascular relaxation in porcine coronary small arteries and rat aortas. Intravenous infusion of Up4A into conscious rats or mice decreases blood pressure, and intravenous bolus injection of Up4A into anesthetized mice increases coronary blood flow, indicating an overall vasodilator influence in vivo. Although Up4A is the first dinucleotide described that contains both purine and pyrimidine moieties, its cardiovascular effects are exerted mainly through activation of purinergic receptors. These effects not only encompass regulation of vascular tone, but also endothelial angiogenesis, smooth muscle cell proliferation and migration, and vascular calcification. Furthermore, this review discusses a potential role for Up4A in cardiovascular pathophysiology, as plasma levels of Up4A are elevated in juvenile hypertensive patients and Up4A-mediated vascular purinergic signaling changes in cardiovascular disease such as hypertension, diabetes, atherosclerosis and myocardial infarction. Better understanding the vascular effect of the novel dinucleotide Up4A and the purinergic signaling mechanisms mediating its effects will enhance its potential as target for treatment of cardiovascular disease.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Fosfatos de Dinucleosídeos/fisiologia , Receptores Purinérgicos/fisiologia , Animais , Sistema Cardiovascular , Humanos , Transdução de Sinais
10.
Rejuvenation Res ; 22(5): 385-389, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30526321

RESUMO

Reduced bioavailability of nitric oxide (NO) is accompanied by endothelial dysfunction, which precedes clinical signs of atherosclerosis. The metalloenzyme arginase reciprocally inhibits the formation of NO and available data demonstrate that arginase contributes to reduced bioavailability of NO and increases the formation of reactive oxygen species. Emerging evidence suggests that arginase thereby plays a key role in the pathophysiology of age-associated vascular complications in animal models. However, the role of arginase in elderly human subjects in vivo with regard to macrovascular endothelial function is unclear. We hypothesized that arginase inhibition improves endothelial function in an age-dependent manner in elderly healthy subjects. Twenty-one subjects ranging from 48 to 75 years of age were included for evaluation of endothelial function using forearm venous occlusion plethysmography. Endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIDV) were evaluated before and after 2-hour intra-arterial infusion of the arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA). Baseline EDV, but not EIDV, was inversely correlated with age (p < 0.05, R = -0.48 and p = 0.62, R = -0.14, respectively). The magnitude of the improvement in EDV induced by arginase inhibition was significantly correlated with age (p < 0.05, R = 0.56), whereas EIDV was not (p = 0.25, R = 0.26). Arginase inhibition improves endothelial function in an age-dependent manner in elderly healthy subjects. The results suggest that arginase is a key factor contributing to endothelial dysfunction and may serve as a future pharmacological target for improving endothelial function in elderly subjects.

11.
Int J Mol Sci ; 19(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544633

RESUMO

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Animais , Diabetes Mellitus Experimental , Fosfatos de Dinucleosídeos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores Purinérgicos/metabolismo , Vasoconstrição/efeitos dos fármacos
13.
JACC Basic Transl Sci ; 3(4): 450-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175269

RESUMO

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

14.
J Am Coll Cardiol ; 72(7): 769-780, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30092954

RESUMO

BACKGROUND: Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM. OBJECTIVES: The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase. METHODS: RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies. RESULTS: Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism. CONCLUSIONS: This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.

15.
J Card Fail ; 24(7): 470-478, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29802896

RESUMO

BACKGROUND: Oxytocin (Oxt) and its receptor (Oxtr) gene system has been implicated in cardiomyogenesis and cardioprotection; however, effects of chronic activation of Oxtr are not known. We generated and investigated transgenic (TG) mice that overexpress Oxtr specifically in the heart. METHODS AND RESULTS: Cardiac-specific overexpression of Oxtr was obtained by having the α-major histocompatibility complex promoter drive the mouse Oxtr gene (α-Mhc-Oxtr). Left ventricular (LV) function and remodeling were assessed by magnetic resonance imaging and echocardiography. In α-Mhc-Oxtr TG mice, LV ejection fraction was severely compromised at 14 weeks of age compared with wild-type (WT) littermates (25 ± 6% vs 63 ± 3%; P < .001). LV end-diastolic volume was larger in the TG mice (103 ± 6 µL vs 67 ± 5 µL; P < .001). α-Mhc-Oxtr TG animals displayed cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes. Mortality of α-Mhc-Oxtr TG animals was 45% compared with 0% (P < .0001) of WT littermates by 20 weeks of age. Most cardiomyocytes of α-Mhc-Oxtr TG animals but not WT littermates (68.0 ± 12.1% vs 5.6 ± 2.4%; P = .008) were positive in staining for nuclear factor of activated T cells (NFAT). To study if thrombin inhibitor prevents thrombus formation, a cohort of 7-week-old α-Mhc-Oxtr TG mice were treated for 12 weeks with AZD0837, a potent thrombin inhibitor. Treatment with AZD0837 reduced thrombus formation (P < .05) and tended to attenuate fibrosis and increase survival. CONCLUSIONS: Cardiac-specific overexpression of Oxtr had negative consequences on LV function and survival in mice. The present findings necessitate further studies to investigate potential adverse effects of chronic Oxt administration. We provide a possible mechanism of Oxtr overexpression leading to heart failure by nuclear factor of activated T cell signaling. The recapitulation of human heart failure and the beneficial effects of the antithrombin inhibitor render the α-Mhc-Oxtr TG mice a promising tool in drug discovery for heart failure.

16.
Redox Biol ; 14: 328-337, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29024896

RESUMO

Endothelial dysfunction is associated with decreased NO bioavailability and impaired activation of the NO receptor soluble guanylate cyclase (sGC) in the vasculature and in platelets. Red blood cells (RBCs) are known to produce NO under hypoxic and normoxic conditions; however evidence of expression and/or activity of sGC and downstream signaling pathway including phopshodiesterase (PDE)-5 and protein kinase G (PKG) in RBCs is still controversial. In the present study, we aimed to investigate whether RBCs carry a functional sGC signaling pathway and to address whether this pathway is compromised in coronary artery disease (CAD). Using two independent chromatographic procedures, we here demonstrate that human and murine RBCs carry a catalytically active α1ß1-sGC (isoform 1), which converts 32P-GTP into 32P-cGMP, as well as PDE5 and PKG. Specific sGC stimulation by NO+BAY 41-2272 increases intracellular cGMP-levels up to 1000-fold with concomitant activation of the canonical PKG/VASP-signaling pathway. This response to NO is blunted in α1-sGC knockout (KO) RBCs, but fully preserved in α2-sGC KO. In patients with stable CAD and endothelial dysfunction red cell eNOS expression is decreased as compared to aged-matched controls; by contrast, red cell sGC expression/activity and responsiveness to NO are fully preserved, although sGC oxidation is increased in both groups. Collectively, our data demonstrate that an intact sGC/PDE5/PKG-dependent signaling pathway exists in RBCs, which remains fully responsive to NO and sGC stimulators/activators in patients with endothelial dysfunction. Targeting this pathway may be helpful in diseases with NO deficiency in the microcirculation like sickle cell anemia, pulmonary hypertension, and heart failure.


Assuntos
Doença da Artéria Coronariana/metabolismo , Eritrócitos/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Adulto , Idoso , Animais , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Humanos , Camundongos , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Transdução de Sinais , Guanilil Ciclase Solúvel/análise
17.
N Engl J Med ; 377(13): 1240-1249, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28844200

RESUMO

BACKGROUND: The clinical effect of routine oxygen therapy in patients with suspected acute myocardial infarction who do not have hypoxemia at baseline is uncertain. METHODS: In this registry-based randomized clinical trial, we used nationwide Swedish registries for patient enrollment and data collection. Patients with suspected myocardial infarction and an oxygen saturation of 90% or higher were randomly assigned to receive either supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered through an open face mask) or ambient air. RESULTS: A total of 6629 patients were enrolled. The median duration of oxygen therapy was 11.6 hours, and the median oxygen saturation at the end of the treatment period was 99% among patients assigned to oxygen and 97% among patients assigned to ambient air. Hypoxemia developed in 62 patients (1.9%) in the oxygen group, as compared with 254 patients (7.7%) in the ambient-air group. The median of the highest troponin level during hospitalization was 946.5 ng per liter in the oxygen group and 983.0 ng per liter in the ambient-air group. The primary end point of death from any cause within 1 year after randomization occurred in 5.0% of patients (166 of 3311) assigned to oxygen and in 5.1% of patients (168 of 3318) assigned to ambient air (hazard ratio, 0.97; 95% confidence interval [CI], 0.79 to 1.21; P=0.80). Rehospitalization with myocardial infarction within 1 year occurred in 126 patients (3.8%) assigned to oxygen and in 111 patients (3.3%) assigned to ambient air (hazard ratio, 1.13; 95% CI, 0.88 to 1.46; P=0.33). The results were consistent across all predefined subgroups. CONCLUSIONS: Routine use of supplemental oxygen in patients with suspected myocardial infarction who did not have hypoxemia was not found to reduce 1-year all-cause mortality. (Funded by the Swedish Heart-Lung Foundation and others; DETO2X-AMI ClinicalTrials.gov number, NCT01787110 .).


Assuntos
Infarto do Miocárdio/terapia , Oxigenoterapia , Idoso , Feminino , Seguimentos , Cardiopatias/diagnóstico , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Oxigenoterapia/efeitos adversos , Modelos de Riscos Proporcionais , Sistema de Registros , Suécia , Falha de Tratamento
18.
Int J Mol Sci ; 18(8)2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28757567

RESUMO

Pulmonary hypertension (PH) is a heterogeneous disorder associated with a poor prognosis. Thus, the development of novel treatment strategies is of great interest. The enzyme arginase (Arg) is emerging as important player in PH development. The aim of the current study was to determine the expression of ArgI and ArgII as well as the effects of Arg inhibition in a rat model of PH. PH was induced in 35 Sprague-Dawley rats by monocrotaline (MCT, 60 mg/kg as single-dose). There were three experimental groups: sham-treated controls (control group, n = 11), MCT-induced PH (MCT group, n = 11) and MCT-induced PH treated with the Arg inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; MCT/NorNoha group, n = 13). ArgI and ArgII expression was determined by immunohistochemistry and Western blot. Right ventricular systolic pressure (RVPsys) was measured and lung tissue remodeling was determined. Induction of PH resulted in an increase in RVPsys (81 ± 16 mmHg) compared to the control group (41 ± 15 mmHg, p = 0.002) accompanied by a significant elevation of histological sum-score (8.2 ± 2.4 in the MCT compared to 1.6 ± 1.6 in the control group, p < 0.001). Both, ArgI and ArgII were relevantly expressed in lung tissue and there was a significant increase in the MCT compared to the control group (p < 0.01). Arg inhibition resulted in a significant reduction of RVPsys to 52 ± 19 mmHg (p = 0.006) and histological sum-score to 5.8 ± 1.4 compared to the MCT group (p = 0.022). PH leads to increased expression of Arg. Arg inhibition leads to reduction of RVPsys and diminished lung tissue remodeling and therefore represents a potential treatment strategy in PH.


Assuntos
Arginase/metabolismo , Arginina/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Monocrotalina/efeitos adversos , Animais , Arginina/administração & dosagem , Arginina/farmacologia , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Ratos Sprague-Dawley , Resultado do Tratamento
19.
Eur J Clin Invest ; 47(9): 638-648, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28683166

RESUMO

BACKGROUND: Novel biomarkers representing different pathobiological pathways and their role in patients with acute myocardial infarction (AMI) were studied. METHODS: We retrospectively analysed serum levels of soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR), heart-type fatty acid-binding protein (H-FABP) and plasma fetuin A in blood of patients with AMI (STEMI, n = 61; NSTEMI, n = 57) compared to controls with excluded coronary artery disease (n = 76). Furthermore, detailed correlation analysis was performed. RESULTS: Compared with controls, in patients with STEMI and NSTEMI higher levels expressed as median of sST2 in pg/mL (STEMI: 13210·9, NSTEMI: 11989·1, control: 5248; P < 0·001), GDF-15 in pg/mL (STEMI: 818·8, NSTEMI 677·5, control 548·6; P < 0·001), suPAR in pg/mL (STEMI: 3461·1, NSTEMI: 3466·7, control: 2463·6; P < 0·001), H-FABP in ng/mL (STEMI: 5·8, NSTEMI: 5·4, control: 0·0; P < 0·001) and lower plasma fetuin A levels in µg/mL (STEMI: 95, NSTEMI: 54, control: 116·6; P < 0·001) were detected. Correlation analysis found clinical and biochemical parameters such as ejection fraction, length of hospital stay, creatine kinase, NT-proBNP and hs Troponin T levels as well as inflammatory markers (CRP, leucocytes) to be significantly correlated with novel biomarkers. CONCLUSION: Plasma levels of novel biomarkers were significantly elevated (sST2, GDF-15, H-FABP, suPAR) or inversely downregulated (fetuin A) in patients with AMI compared to a control group with excluded coronary artery disease. Significant correlations with various clinical parameters and standard biochemical markers were found.


Assuntos
Proteína 3 Ligante de Ácido Graxo/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Infarto do Miocárdio/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , alfa-2-Glicoproteína-HS/metabolismo , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Creatina Quinase/sangue , Feminino , Humanos , Tempo de Internação , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Fragmentos de Peptídeos/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Volume Sistólico , Troponina T/sangue
20.
J Cardiovasc Magn Reson ; 19(1): 55, 2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28750637

RESUMO

BACKGROUND: Clinical outcome following acute myocardial infarction is predicted by final infarct size evaluated in relation to left ventricular myocardium at risk (MaR). Contrast-enhanced steady-state free precession (CE-SSFP) cardiovascular magnetic resonance imaging (CMR) is not widely used for assessing MaR. Evidence of its utility compared to traditional assessment methods and as a surrogate for clinical outcome is needed. METHODS: Retrospective analysis within a study evaluating post-conditioning during ST elevation myocardial infarction (STEMI) treated with coronary intervention (n = 78). CE-SSFP post-infarction was compared with angiographic jeopardy methods. Differences and variability between CMR and angiographic methods using Bland-Altman analyses were evaluated. Clinical outcomes were compared to MaR and extent of infarction. RESULTS: MaR showed correlation between CE-SSFP, and both BARI and APPROACH scores of 0.83 (p < 0.0001) and 0.84 (p < 0.0001) respectively. Bias between CE-SSFP and BARI was 1.1% (agreement limits -11.4 to +9.1). Bias between CE-SSFP and APPROACH was 1.2% (agreement limits -13 to +10.5). Inter-observer variability for the BARI score was 0.56 ± 2.9; 0.42 ± 2.1 for the APPROACH score; -1.4 ± 3.1% for CE-SSFP. Intra-observer variability was 0.15 ± 1.85 for the BARI score; for the APPROACH score 0.19 ± 1.6; and for CE-SSFP -0.58 ± 2.9%. CONCLUSION: Quantification of MaR with CE-SSFP imaging following STEMI shows high correlation and low bias compared with angiographic scoring and supports its use as a reliable and practical method to determine myocardial salvage in this patient population. TRIAL REGISTRATION: Clinical trial registration information for the parent clinical trial: Karolinska Clinical Trial Registration (2008) Unique identifier: CT20080014. Registered 04th January 2008.


Assuntos
Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Idoso , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Intervenção Coronária Percutânea , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Fatores de Tempo , Resultado do Tratamento
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