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- Mahdi, A., et al.
(author)
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The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia
- 2023
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 293:2, s. 228-245
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Journal article (peer-reviewed)abstract
- Background Patients with familial hypercholesterolemia (FH) display high levels of low-density lipoprotein cholesterol (LDL-c), endothelial dysfunction, and increased risk of premature atherosclerosis. We have previously shown that red blood cells (RBCs) from patients with type 2 diabetes induce endothelial dysfunction through increased arginase 1 and reactive oxygen species (ROS). Objective To test the hypothesis that RBCs from patients with FH (FH-RBCs) and elevated LDL-c induce endothelial dysfunction. Methods and results FH-RBCs and LDL-c >5.0 mM induced endothelial dysfunction following 18-h incubation with isolated aortic rings from healthy rats compared to FH-RBCs and LDL-c <2.5 mM or RBCs from healthy subjects (H-RBCs). Inhibition of vascular but not RBC arginase attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. Furthermore, arginase 1 but not arginase 2 was elevated in the vasculature of aortic segments after incubation with FH-RBCs and LDL-c >5.0 mM. A superoxide scavenger, present throughout the 18-h incubation, attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. ROS production was elevated in these RBCs in comparison with H-RBCs. Scavenging of vascular ROS through various antioxidants also attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. This was corroborated by an increase in the lipid peroxidation product 4-hydroxynonenal. Lipidomic analysis of RBC lysates did not reveal any significant changes across the groups. Conclusion FH-RBCs induce endothelial dysfunction dependent on LDL-c levels via arginase 1 and ROS-dependent mechanisms.
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- Jernberg, T., et al.
(author)
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Long-Term Effects of Oxygen Therapy on Death or Hospitalization for Heart Failure in Patients With Suspected Acute Myocardial Infarction
- 2018
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In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 138:24, s. 2754-2762
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Journal article (peer-reviewed)abstract
- BACKGROUND: In the DETO2X-AMI trial (Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction), we compared supplemental oxygen with ambient air in normoxemic patients presenting with suspected myocardial infarction and found no significant survival benefit at 1 year. However, important secondary end points were not yet available. We now report the prespecified secondary end points cardiovascular death and the composite of all-cause death and hospitalization for heart failure. METHODS: In this pragmatic, registry-based randomized clinical trial, we used a nationwide quality registry for coronary care for trial procedures and evaluated end points through the Swedish population registry (mortality), the Swedish inpatient registry (heart failure), and cause of death registry (cardiovascular death). Patients with suspected acute myocardial infarction and oxygen saturation of >= 90% were randomly assigned to receive either supplemental oxygen at 6 L/min for 6 to 12 hours delivered by open face mask or ambient air. RESULTS: A total of 6629 patients were enrolled. Acute heart failure treatment, left ventricular systolic function assessed by echocardiography, and infarct size measured by high-sensitive cardiac troponin T were similar in the 2 groups during the hospitalization period. All-cause death or hospitalization for heart failure within 1 year after randomization occurred in 8.0% of patients assigned to oxygen and in 7.9% of patients assigned to ambient air (hazard ratio, 0.99; 95% CI, 0.84-1.18; P=0.92). During long-term follow-up (median [range], 2.1 [1.0-3.7] years), the composite end point occurred in 11.2% of patients assigned to oxygen and in 10.8% of patients assigned to ambient air (hazard ratio, 1.02; 95% CI, 0.88-1.17; P=0.84), and cardiovascular death occurred in 5.2% of patients assigned to oxygen and in 4.8% assigned to ambient air (hazard ratio, 1.07; 95% CI, 0.87-1.33; P=0.52). The results were consistent across all predefined subgroups. CONCLUSIONS: Routine use of supplemental oxygen in normoxemic patients with suspected myocardial infarction was not found to reduce the composite of all-cause mortality and hospitalization for heart failure, or cardiovascular death within 1 year or during long-term follow-up.
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- Jiao, T, et al.
(author)
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Erythrocytes from patients with ST-elevation myocardial infarction induce cardioprotection through the purinergic P2Y13 receptor and nitric oxide signaling
- 2022
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In: Basic research in cardiology. - : Springer Science and Business Media LLC. - 1435-1803 .- 0300-8428. ; 117:1, s. 46-
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Journal article (peer-reviewed)abstract
- Red blood cells (RBCs) are suggested to play a role in cardiovascular regulation by exporting nitric oxide (NO) bioactivity and ATP under hypoxia. It remains unknown whether such beneficial effects of RBCs are protective in patients with acute myocardial infarction. We investigated whether RBCs from patients with ST-elevation myocardial infarction (STEMI) protect against myocardial ischemia–reperfusion injury and whether such effect involves NO and purinergic signaling in the RBCs. RBCs from patients with STEMI undergoing primary coronary intervention and healthy controls were administered to isolated rat hearts subjected to global ischemia and reperfusion. Compared to RBCs from healthy controls, RBCs from STEMI patients reduced myocardial infarct size (30 ± 12% RBC healthy vs. 11 ± 5% RBC STEMI patients, P < 0.001), improved recovery of left-ventricular developed pressure and dP/dt and reduced left-ventricular end-diastolic pressure in hearts subjected to ischemia–reperfusion. Inhibition of RBC NO synthase with L-NAME or soluble guanylyl cyclase (sGC) with ODQ, and inhibition of cardiac protein kinase G (PKG) abolished the cardioprotective effect. Furthermore, the non-selective purinergic P2 receptor antagonist PPADS but not the P1 receptor antagonist 8PT attenuated the cardioprotection induced by RBCs from STEMI patients. The P2Y13 receptor was expressed in RBCs and the cardioprotection was abolished by the P2Y13 receptor antagonist MRS2211. By contrast, perfusion with PPADS, L-NAME, or ODQ prior to RBCs administration failed to block the cardioprotection induced by RBCs from STEMI patients. Administration of RBCs from healthy subjects following pre-incubation with an ATP analog reduced infarct size from 20 ± 6 to 7 ± 2% (P < 0.001), and this effect was abolished by ODQ and MRS2211. This study demonstrates a novel function of RBCs in STEMI patients providing protection against myocardial ischemia–reperfusion injury through the P2Y13 receptor and the NO–sGC–PKG pathway.
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- Bulhak, A, et al.
(author)
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Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation
- 2007
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In: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 292:6, s. H3158-H3163
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Journal article (peer-reviewed)abstract
- Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 ± 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 ± 2% ( P < 0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 ± 2%, P < 0.01 vs. rosuvastatin) but not methanol (65 ± 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 ± 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium ( P < 0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.
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- Gronros, J, et al.
(author)
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Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats
- 2011
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In: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 300:4, s. H1174-H1181
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Journal article (peer-reviewed)abstract
- Nitric oxide (NO) is crucial for maintaining normal endothelial function and vascular integrity. Increased arginase activity in diabetes might compete with NO synthase (NOS) for their common substrate arginine, resulting in diminished production of NO. The aim of this study was to evaluate coronary microvascular function in type 2 diabetic Goto-Kakizaki (GK) rats using in vivo coronary flow velocity reserve (CFVR) and the effect of arginase inhibition to restore vascular function. Different groups of GK and Wistar rats were given vehicle, the arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA), l-arginine, and the NOS inhibitor NG-monomethyl -l-arginine (l-NMMA). GK rats had impaired CFVR compared with Wistar rats (1.31 ± 0.09 vs. 1.87 ± 0.05, P < 0.001). CFVR was restored by nor-NOHA treatment compared with vehicle in GK rats (1.71 ± 0.13 vs. 1.23 ± 0.12, P < 0.05) but remained unchanged in Wistar rats (1.88 ± 0.10 vs. 1.79 ± 0.16). The beneficial effect of nor-NOHA in GK rats was abolished after NOS inhibition. CFVR was not affected by arginine compared with vehicle. Arginase II expression was increased in the aorta and myocardium from GK rats compared with Wistar rats. Citrulline-to-ornithine and citrulline-to-arginine ratios measured in plasma increased significantly more in GK rats than in Wistar rats after nor-NOHA treatment, suggesting a shift of arginine utilization from arginase to NOS. In conclusion, coronary artery microvascular function is impaired in the type 2 diabetic GK rat. Treatment with nor-NOHA restores the microvascular function by a mechanism related to increased utilization of arginine by NOS and increased NO availability.
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- Johansson, BL, et al.
(author)
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C-peptide increases forearm blood flow in patients with type 1 diabetes via a nitric oxide-dependent mechanism
- 2003
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 285:4, s. E864-E870
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Journal article (peer-reviewed)abstract
- Proinsulin C-peptide has been shown to increase muscle blood flow in type 1 diabetic patients. The underlying mechanism is not fully understood. The aim of this study was to evaluate if the vasodilator effect of C-peptide is mediated by nitric oxide (NO). Eleven type 1 diabetic patients were studied two times and randomized to administration of intravenous and intra-arterial infusion of C-peptide or saline. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during infusion of C-peptide or saline before, during, and after NO synthase (NOS) blockade. Endothelium-dependent and -independent vasodilatation was evaluated by administration of acetylcholine and sodium nitroprusside, respectively. FBF increased by 35% during intravenous C-peptide ( P < 0.01) but not during saline infusion (–2%, not significant). NOS blockade resulted in a more pronounced reduction in FBF during intravenous C-peptide than during saline infusion (–41 vs. –26%, P < 0.05). Intra-arterial C-peptide failed to increase FBF during NOS blockade. However, when C-peptide was given after the recovery from NOS blockade, FBF rose by 30% ( P < 0.001). The vasodilator effects of acetylcholine and nitroprusside were not influenced by C-peptide. It is concluded that the stimulatory effect of C-peptide on FBF in type 1 diabetic patients is mediated via the NO system and that C-peptide increases basal endothelial NO levels.
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- Kjellberg, A, et al.
(author)
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Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial
- 2022
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In: BMJ open. - : BMJ. - 2044-6055. ; 12:11, s. e061870-
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Journal article (peer-reviewed)abstract
- Long COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL.Methods and analysisA randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board.Ethics and disseminationThe trial is approved by the Swedish National Institutional Review Board (2021–02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access.Trial registration numberNCT04842448.
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