Search

Red blood cells (RBCs) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBCs were co-incubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBCs from patients with T2DM (T2DM RBC) and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human T2DM RBC than in RBCs from healthy subjects (H RBC). Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in H RBC or RBCs from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in non-diabetic patients. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBCs via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

Background: Vascular injury has been implicated as a major cause of clinical complications in patients with coronavirus disease 2019 (COVID-19) based on autopsy studies showing destruction of the endothelial architecture. Red blood cells (RBCs) are affected by COVID-19 with alterations in their structure and function, possibly altering disease progress. Objectives: This study was designed to test the hypothesis of persistent endothelial dysfunction and that RBCs act as mediators of endothelial dysfunction in COVID-19. Methods and results: COVID-19 patients displayed profound endothelial dysfunction in vivo assessed with pulse amplitude tonometry, both in the acute phase and at follow-up four months later. RBCs from COVID-19 patients in the acute phase incubated with healthy rat aorta induced severe endothelial dysfunction ex vivo compared to RBCs from healthy subjects. Further, these RBCs induced upregulation of vascular arginase 1 and oxidative stress. Consequently, inhibition of vascular arginase or superoxide attenuated endothelial dysfunction induced by RBCs from COVID-19 patients. These RBCs were characterized by increased production of reactive oxygen species and reduced export of the nitric oxide metabolite nitrate. RBCs from COVID-19 patients at follow-up did not affect endothelial function. Pre-incubation of RBCs from healthy subjects with interferon-γ impaired endothelial function.Conclusions: This study demonstrates the presence of persistent endothelial dysfunction in an otherwise mainly healthy population hospitalized for COVID-19, and clearly implicates a central role of RBCs as mediators of endothelial injury. These data shed light on a new pathological mechanism underlying vascular dysfunction in COVID-19 and may lay the foundation for future therapeutic developments.

Background Vascular injury has been implicated as a major cause of clinical complications in patients with coronavirus disease 2019 (COVID-19). Autopsy studies have revealed destruction of the endothelial cell lining, which might explain cardiovascular alterations arising from the infection. However, data demonstrating endothelial dysfunction during ongoing infection are sparse, and the underlying mechanisms are still largely unknown. Red blood cells (RBCs) are affected by COVID-19 with alterations in their structure and function, possibly contributing to vascular injury via increased oxidative stress. Purpose To determine the presence of endothelial dysfunction in patients with COVID-19 and to explore the RBC as a possible mediator of such dysfunction. Methods The study was performed on 17 patients hospitalized for moderate COVID-19 infection and age- and sex-matched healthy subjects. Inclusion criteria of the COVID-19 patients were PCR-verified SARS-CoV2 infection, pulmonary infiltrates on x-ray, oxygen demand during hospital stay and ≤ one cardiovascular co-morbidity. Microvascular endothelial function in vivo was assessed with a pulse amplitude tonometry device on each index finger at baseline and during reactive hyperemia and expressed as reactive hyperemia index (RHI). RBCs from COVID-19 patients (C19-RBCs) and healthy subjects (H-RBCs) were incubated with isolated rat aortic segments for evaluation of endothelium-dependent and -independent relaxation. Results COVID-19 patients displayed profound impairment in endothelial function in vivo with RHI 1.56 (1.30–1.81, median and interquartile range) compared to healthy subjects 2.36 (1.97–2.79, p Conclusions This study demonstrates the presence of marked endothelial dysfunction in an otherwise mainly healthy patient group hospitalized for COVID-19, and clearly implicates a central role of the RBC as a mediator of endothelial injury through enhancement of reactive oxygen species and arginase. These data shed light on a new pathological mechanism underlying vascular dysfunction in COVID-19 patients and may lay the foundation for future therapeutic developments. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung foundationSwedish Research Council

Background: Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin β chain (β93C) 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 β93 cysteine had been replaced with alanine (β93A) 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 (β93C) 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 β93A 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 β93C and β93A 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 β93C and β93A 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 β93C and β93A mice. Conclusions: RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the β93 cysteine of Hb.

It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X7R but not P2Y6R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X7R but not P2Y6R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X7R but not P2Y6R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D.

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.

Aim: RhoA/Rho-associated kinase and arginase are implicated in vascular complications in diabetes. This study investigated whether RhoA/Rho-associated kinase and arginase inhibition protect from myocardial ischaemia–reperfusion injury in type 1 diabetes and the mechanisms behind these effects. Methods: Rats with streptozotocin-induced type 1 diabetes and non-diabetic rats were subjected to 30 min myocardial ischaemia and 2 h reperfusion after being randomized to treatment with (1) saline, (2) RhoA/Rho-associated kinase inhibitor hydroxyfasudil, (3) nitric oxide synthase inhibitor NG-monomethyl-l-arginine monoacetate followed by hydroxyfasudil, (4) arginase inhibitor N-omega-hydroxy-nor-l-arginine, (5) NG-monomethyl-l-arginine monoacetate followed by N-omega-hydroxy-nor-l-arginine or (6) NG-monomethyl-l-arginine monoacetate given intravenous before ischaemia. Results: Myocardial arginase activity, arginase 2 expression and RhoA/Rho-associated kinase activity were increased in type 1 diabetes ( p Conclusion: Inhibition of either RhoA/Rho-associated kinase or arginase protects from ischaemia–reperfusion injury in rats with type 1 diabetes via a nitric oxide synthase–dependent pathway. These results suggest that inhibition of RhoA/Rho-associated kinase and arginase constitutes a potential therapeutic strategy to protect the diabetic heart against ischaemia–reperfusion injury.

Background Reduced bioavailability of nitric oxide (NO) is a key factor behind coronary artery disease and ischemic heart disease. Besides being produced from L-arginine by NO synthase, reduction of nitrate/nitrite to NO is also an important pathway for NO generation, especially during hypoxic/ischemic conditions. Existing evidences suggest that dietary nitrate improves endothelial function and ischemic tolerance via a NO-dependent mechanism. Recent data indicate that red blood cells (RBCs) are an important source of NO bioactivity that protects the heart from ischemia-reperfusion injury. It is unknown whether dietary nitrate exerts cardioprotection by increasing export of RBC NO bioactivity. Purpose To investigate whether dietary nitrate protects the heart against ischemia-reperfusion injury via a mechanism mediated by RBCs. Methods Patients with mild hypertension (systolic blood pressure >130, ≤159 mmHg) were randomly assigned to three groups after a 2-week run-in period on a diet low in nitrate: group 1 received nitrate-rich vegetables (green leafy, ∼150 g/day) plus capsules with placebo salt (KCl), group 2 received low nitrate vegetables (cherry tomato, sweet corn, capsicum, carrot, ∼150 g/day) and capsules with nitrate salt (KNO3, 300mg) and group 3 received low nitrate vegetables and placebo capsules for 5 weeks. The nitrate content of the pills and nitrate-rich vegetables were precisely matched. As a pre-specified substudy, RBCs were collected blindly from 48 subjects before (baseline) and after the 5-week treatment (follow-up). The RBCs were given to isolated Langendorff-perfused rat hearts at the onset of ischemia with and without the soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ). The hearts were subjected to 25 min global ischemia following 60 min reperfusion. Left ventricular developed pressure (LVDP) was recorded as an indicator of cardiac function. Results The recovery in LVDP during reperfusion following global ischemia in hearts given RBCs collected at baseline was similar in the three groups (Fig. A). Of note, post-ischemic recovery of LVDP was significantly improved by administration of RBCs from patients randomized to high nitrate vegetables or nitrate capsule compared to the group randomized to low nitrate and placebo (Fig. B). There was no difference in LVDP recovery between the groups receiving high nitrate vegetables or nitrate capsule (Fig. B). The nitrate-induced improvement in post-ischemic cardiac recovery was totally abolished by the sGC inhibitor ODQ (Fig. C), indicating that the protective effect induced by RBCs from subjects given nitrate is NO-sGC dependent. Conclusion Dietary nitrate in the form of leafy vegetables induces protection against myocardial ischemia-reperfusion injury via a mechanism involving the NO-sGC signaling pathway in RBCs.

Background Inorganic nitrate has been shown to exert beneficial cardiovascular effects, which are thought to be mediated via sequential reduction of nitrate to nitrite and nitric oxide (NO). We have previously reported that hearts from type 2 diabetic db/db mice have impaired cardiac ischemic tolerance and that this effect involves reduced export of NO-like bioactivity from red blood cells (RBCs). It remains unknown whether nitrate supplementation may affect cardiac ischemic tolerance in diabetes through interference with RBC function. Purpose To test the hypothesis that dietary nitrate supplementation improves cardiac ischemic tolerance of hearts via an effect mediated through RBCs in type 2 diabetes. Methods Type 2 diabetic (db/db) and wild type (WT) mice on nitrate-free chow were treated with vehicle or nitrate (1 mM) in the drinking water for 4 weeks. Hearts were isolated and perfused using the Langendorff technique. After 30 min stabilization, the hearts were subjected to 40 min global ischemia followed by 60 min reperfusion. In protocol 1, isolated hearts from db/db and WT mice given vehicle or nitrate were perfused with buffer. In protocol 2, only hearts from untreated WT mice were used. Washed RBCs from WT or db/db mice treated with vehicle or nitrate were administered to WT hearts at the onset of ischemia with and without the soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ). In both protocols post-ischemic recovery of cardiac function was evaluated by determination of left ventricular developed pressure (LVDP). Results In Protocol 1, post-ischemic recovery of LVDP was impaired in hearts from db/db mice in comparison with hearts from WT mice (Fig. A). Dietary nitrate restored the ischemic tolerance of hearts from db/db mice but did not affect post-ischemic recovery of hearts from WT mice (Fig. A). In Protocol 2, administration of RBCs collected from vehicle-treated db/db mice significantly impaired post-ischemic recovery of hearts from WT mice (Fig. B). Notably, administration of RBCs from nitrate-treated db/db mice completely reversed the impairment of post-ischemic cardiac function induced by diabetic RBCs (Fig. B). Interestingly, post-ischemic cardiac function did not differ between hearts given RBCs from nitrate-treated db/db and WT mice (Fig. B). The protective effect of RBCs from nitrate-treated mice was abolished by pre-incubation of the RBCs with ODQ, an inhibitor of soluble guanylate cyclase (sGC) (Fig. C). By contrast, pretreatment of isolated WT hearts with ODQ failed to block the protective effect of RBCs from nitrate-treated mice (Fig C) indicating that sGC in the RBC but not in the heart is critical for nitrate-induced cardiac protection. Conclusion Dietary nitrate restores cardiac ischemic tolerance in db/db mice and protects the heart against ischemia–reperfusion injury via an RBC NO-sGC pathway.

Red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM) induce endothelial dysfunction and impair cardiac function following ischemia via increase in RBC arginase and oxidative stress. Here, we aimed to elucidate whether the effect of RBC-mediated cardiac impairment following ischemia and endothelial dysfunction in T2DM is dependent on glycemic control. Patients with T2DM at poor glycemic control (T2DM PGC) and at improvement in glycemic control (T2DM IGC) and healthy subjects were recruited. Isolated RBCs from subjects were incubated with aortic rings from healthy wild-type rats with subsequent evaluation of endothelium-dependent relaxation (EDR) using wire myograph. Moreover, RBCs were administered to isolated wild-type rat hearts with subsequent evaluation of left ventricular developed pressure (LVDP) during reperfusion using Langendorff setup. In separate experiments, RBCs were preincubated with an arginase inhibitor before perfusion. Blood glucose and glycated hemoglobin were 33 and 26%, respectively, lower in T2DM IGC compared with those in T2DM PGC. RBCs from T2DM PGC and T2DM IGC impaired EDR to a similar magnitude compared with RBCs from healthy subjects. LVDP was significantly impaired in hearts given RBCs from T2DM PGC as compared with those from healthy subjects. The impairment of LVDP induced by T2DM PGC was attenuated by RBCs from T2DM IGC. Arginase inhibition improved LVDP to a similar extent between T2DM PGC and IGC groups. These observations indicate that glycemic control abrogate the impairment in postischemic recovery but not endothelial dysfunction induced by RBCs from T2DM. Moreover, inhibition of RBC arginase improves cardiac function irrespective of glycemic control.

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.

Background Reduced bioavailability of nitric oxide (NO) is a key factor contributing to myocardial ischemia and reperfusion injury. The mechanism behind the reduction of NO is related to deficiency of the NO synthase (NOS) substrate l-arginine and cofactor tetrahydrobiopterin (BH4) resulting in NOS uncoupling. The aim of the study was to investigate if the combination of l-arginine and BH4 given iv or intracoronary before reperfusion protects from reperfusion injury. Methods Sprague-Dawley rats and pigs were subjected to myocardial ischemia and reperfusion. Rats received vehicle, l-arginine, BH4, l-arginine + BH4 with or without the NOS-inhibitor L-NMMA iv 5 min before reperfusion. Pigs received infusion of vehicle, l-arginine, BH4 or l-arginine + BH4 into the left main coronary artery for 30 min starting 10 min before reperfusion. Results Infarct size was significantly smaller in the rats (50 ± 2%) and pigs (54 ± 5%) given l-arginine + BH4 in comparison with the vehicle groups (rats 65 ± 3% and pigs 86 ± 5%, P < 0.05). Neither l-arginine nor BH4 alone significantly reduced infarct size. Administration of L-NMMA abrogated the cardioprotective effect of l-arginine + BH4. Myocardial BH4 levels were 3.5- to 5-fold higher in pigs given l-arginine + BH4 and BH4 alone. The generation of superoxide in the ischemic-reperfused myocardium was reduced in pigs treated with intracoronary l-arginine + BH4 versus the vehicle group (P < 0.05). Conclusion Administration of l-arginine + BH4 before reperfusion protects the heart from ischemia-reperfusion injury. The cardioprotective effect is mediated via NOS-dependent pathway resulting in diminished superoxide generation. © 2013 Elsevier Ireland Ltd.

Aim: To investigate whether ischaemic post-conditioning (IPoC) combined with i.v. infusion of the nitric oxide (NO) substrate l-arginine at the onset of reperfusion exerts cardioprotective effect that is superior to either treatment given separately. Methods: Twenty-six anesthetized pigs were subjected to coronary artery (left anterior descending artery, LAD) ligation for 40 min followed by 4 h reperfusion. The pigs were randomized into five different groups receiving either i.v. vehicle, i.v. l-arginine, IPoC 4 × 60 s together with i.v. vehicle or IPoC together with i.v. l-arginine and a group with IPoC 8 × 30 s. All infusions were started 10 min before reperfusion. Results: The infarct size of the vehicle group was 82 ± 4% of the area at risk. l-Arginine alone (79 ± 8%), IPoC 4 × 60 s vehicle (86 ± 3%) or IPoC 8 × 30 s vehicle (94 ± 7%) did not affect infarct size. l-Arginine together with IPoC significantly reduced infarct size to 59 ± 4% (P

Aims: Adenosine is involved in classic pre-conditioning (PC) in most species, acting through especially adenosine A 1 and A 3 receptors. We studied whether the adenosine A 1 receptor (A 1 R) was important for remote, delayed adaptation to ischaemia using a mouse with targeted deletion of the A 1 R gene. Methods: Remote, delayed adaptation was evoked by brain ischaemia (BIPC) through bilateral ligation of the internal carotid arteries. Through microdialysis probes placed in the brain and the abdominal aorta, we found that plasma adenosine increased following carotid artery ligation. Twenty-four hours after ligation, hearts were isolated, Langendorff perfused and subjected to 40 min global ischaemia and 60 min reperfusion. Hearts from sham operated and BIPC animals either with (A 1 R +/+ ) or without (A 1 R -/- ) the gene for the adenosine A 1 R were compared with each other. Results: In wild types, BIPC reduced infarct size and improved functional recovery during reperfusion, but BIPC did not protect hearts of A 1 R -/- mice. There were no significant differences between sham-operated A 1 R +/+ and A 1 R -/- in recovery of function or infarct size. The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinasel/2 (ERK1/2), p38 and c-jun N-terminal kinase (JNK) were phosphorylated during reperfusion of sham treated hearts. The increase in ERK1/2 and p38 phosphorylation detected was attenuated in hearts of BIPC or A 1 R -/- animals. Conclusion: During BIPC adenosine acting on the A 1 R appears necessary for myocardial protection. MAPK signalling may possibly be involved in organ protection during the delayed phase of remote, delayed adaptation.

BackgroundPharmacological inhibition of arginase and remote ischemic perconditioning (RIPerc) are known to protect the heart against ischemia/reperfusion (IR) injury.PurposeThe objective of this study was to investigate whether (1) peroxynitrite-mediated RhoA/Rho associated kinase (ROCK) signaling pathway contributes to arginase upregulation following myocardial IR; (2) the inhibition of this pathway is involved as a cardioprotective mechanism of remote ischemic perconditioning and (3) the influence of diabetes on these mechanisms.MethodsAnesthetized rats were subjected to 30 min left coronary artery ligation followed by 2 h reperfusion and included in two protocols. In protocol 1 rats were randomized to 1) control IR, 2) RIPerc induced by bilateral femoral artery occlusion for 15 min during myocardial ischemia, 3) RIPerc and administration of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), 4) administration of the ROCK inhibitor hydroxyfasudil or 5) the peroxynitrite decomposition catalyst FeTPPS. In protocol 2 non-diabetic and type 1 diabetic rats were randomosed to IR or RIPerc as described above.ResultsInfarct size was significantly reduced in rats treated with FeTPPS, hydroxyfasudil and RIPerc compared to controls (PConclusionArginase is activated by peroxynitrite/ROCK signaling cascade in myocardial IR. RIPerc protects against IR injury via a mechanism involving inhibition of this pathway and enhanced eNOS activation. The beneficial effect and associated molecular changes of RIPerc is abolished in type 1 diabetes.

Two distinct enzymes of arginase (1 and 2) are critically regulating nitric oxide (NO) bioavailability by competing with NO synthase for their common substrate l-arginine. Increased expression and activity of arginase is observed in atherosclerosis and myocardial ischemia-reperfusion (I/R). Several studies have demonstrated a key pathophysiological role of increased activity of arginase during I/R. Pharmacological inhibition of arginase results in restoration of NO availability and salvage of myocardium during I/R. Arginase inhibition might be a promising therapeutic strategy for the limitation of myocardial injury in acute myocardial infarction. Current understanding of the role of arginase and efficacy of arginase inhibition during myocardial I/R is reviewed in the present article.

The paper adopts an adaptive nonlinear algorithm for process monitoring and fault diagnosis, and the purpose of fault diagnosis is obtained through acquiring the sensor data, various basic elements in the identification process, events and trends analysis. The fault class knowledge base is formed by using the automated knowledge base development framework (AKDF), and the algorithm adoptes neural network identification elements. The paper has discussed the minimum and maximum length of adaptive window distinguished by fault signal, the probability of fault is got by referring to the probabilities of all kinds of sensor fault classification in knowledge base. The paper has made comparisons on the diagnosis cases which have 20 sensor in the conditions of simple deviation to complex fault and the percent of noise from 0 to 5%, the result shows that the performance of adaptive trend identification is better than fixed window method, ASTRA can properly diagnose all events included in the historical database, and it can tell the unknown fault class.