Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxiainduced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1␤, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC Ϫ/Ϫ , and NLRP3 Ϫ/Ϫ mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC Ϫ/Ϫ mice was significantly lower than in WT exposed to hypoxia (40.8 Ϯ 1.5 mmHg vs. 55.8 Ϯ 2.4 mmHg, P Ͻ 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3Ϫ/Ϫ mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1␤ in WT and NLRP3 Ϫ/Ϫ mice, this response was absent in ASC Ϫ/Ϫ mice. Moreover, ASC Ϫ/Ϫ mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.inflammation; innate immunity; pulmonary vasculature PULMONARY HYPERTENSION can be a life-threatening condition leading to right-sided heart failure and premature death (5, 40). The pathogenesis of the various forms of pulmonary hypertension is not fully known, and insight into disease mechanisms is important for the development of improved treatment options for this severe condition. The role and importance of inflammation and immune activation in the development of pulmonary hypertension are not fully understood; however, inflammation has emerged as an important player. Clinically, increased circulating levels of IL-1␤ and IL-18 have been observed in patients with pulmonary arterial hypertension, indicating that inflammasomes can be activated in this condition (18,41). It is well known that innate immunity is activated in response to infection. However, in the last decade, new knowledge has emerged demonstrating that inflammatory pathways can also be activated as a result of cellular stress during sterile inflammation and that these inflammatory responses involve activation of inflammasomes (27). Inflammasome...

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Aquaporins (AQPs) are channel-forming membrane proteins highly permeable to water. AQP4 is found in mammalian hearts; however, its expression sites, regulation and function are largely unknown. The aim was to investigate cardiac AQP4 expression in humans and mice, its regulation by ischemia and hypoxia, and in particular its role in cardiac ischemic injury using AQP4 knockout (KO) mice. Comparable levels of AQP4 were detected by Western blot and qPCR in biopsies from human donor hearts and wild type C57Bl6 mouse hearts. In mice, AQP4 was expressed on cardiomyocyte plasmalemma (qPCR, Western blot, immunogold), and its mRNA decreased following ischemia/reperfusion (isolated hearts, p = 0.02) and after normobaric hypoxia in vivo (oxygen fraction 10 % for 1 week, p < 0.001). Isolated hearts from AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size (p = 0.05) and attenuated left ventricular end-diastolic pressure during reperfusion (p = 0.04). Infarct size was also reduced in AQP4 KO mice 24 h after left coronary artery ligation in vivo (p = 0.036). AQP4 KO hearts had no compensatory change in AQP1 protein expression. AQP4 KO cardiomyocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture. AQP4 is expressed in human and mouse hearts, in the latter confined to the cardiomyocyte plasmalemma. AQP4 mRNA expression is downregulated by hypoxia and ischemia. Deletion of AQP4 is protective in acute myocardial ischemia-reperfusion, and this molecule might be a future target in the treatment of acute myocardial infarction.

Background: High blood pressure (BP) is associated with poor outcome in acute spontaneous intracerebral hemorrhage. Little is known about the predictive value of prehospital BP in intracerebral hemorrhage. We aimed to investigate the relationship between prehospital BP and clinical and radiological outcomes. Methods: This is a retrospective, hospital-based study of all adult intracerebral hemorrhage patients admitted within 24 hours of symptom onset to a large primary stroke centre during 2012 to 2019. The first prehospital and on-admission BP were recorded as systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. The absolute differences between prehospital and on-admission BP were calculated (BP change ). Primary outcomes were in-hospital death, early neurological deterioration, and hematoma expansion. Associations between prehospital BP, BP change , and outcomes were explored by regression with adjustment for relevant confounders. Results: We included 426 patients aged median 76 (interquartile range 67–85) years and 203 (48%) were female. Median prehospital systolic BP was 179 (interquartile range 158–197) and diastolic BP was 100 (interquartile range 86–112) mm Hg. In-hospital death occurred in 121/426 (28%), early neurological deterioration in 107/295 (36%), and hematoma expansion in 50/185 (27%) patients. There were linear associations between 5 mm Hg increment of prehospital systolic BP (odds ratio 1.06, [95% CI, 1.01–1.12]) and mean arterial pressure (odds ratio 1.08, [95% CI, 1.01–1.15]) and in-hospital death, and between 5 mm Hg increment of prehospital diastolic BP (odds ratio 1.10, [95% CI, 1.00–1.21]) and mean arterial pressure (odds ratio 1.09, [95% CI, 1.00–1.18]) and hematoma expansion. There was a nonlinear association between prehospital systolic BP and in-hospital death. No consistent associations between prehospital BP change and outcomes were found. Conclusions: In patients with acute intracerebral hemorrhage, elevated prehospital BP parameters were associated with in-hospital death and hematoma expansion. Changes in prehospital BP were not consistently associated with outcome. A possible U-shaped association between prehospital BP and in-hospital death needs further investigation.

Neutralization of IL-18 during alveolar hypoxia improves LV diastolic function and partly prevents RV hypertrophy.

Interleukin (IL)-18 is a pro-inflammatory cytokine suggested to be involved in the development of pulmonary emphysema and inflammation. Studies involving immunology and cancer have revealed that IL-18 can have synergistic effects with IL-12. We have studied the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and whether IL-18 and IL-12, alone or in combination, have the ability to initiate the induction of mediators related to the development of emphysema and inflammation. The expression of the IL-18R was abundant in lungs compared to other organs (heart, liver, and spleen), and the IL-12R was also expressed in lung tissue. Mice treated with i.p. injection of recombinant murine IL-18 or IL-12 expressed significantly higher pulmonary mRNA levels of the matrix degrading enzymes metalloproteinase (MMP) 12 and cathepsin S, in addition to interferon-γ, tumor necrosis factor-α, and CXC chemokine ligand 9 (CXCL9) (all P < .05) than controls (received PBS). Treatment with IL-18 and IL-12 in combination showed an even more pronounced induction of these mediators, as well as a significant increase in MMP-9, IL-6, IL-1β, and transforming growth factor-β (P < .05). Furthermore, cellular apoptosis in lung tissue was induced. Immunohistochemical analysis revealed T-cell infiltration in pulmonary vessels following co-stimulation. In summary, IL-18 and IL-12 exert a synergistic effect on the lungs by inducing MMPs, cathepsins S, and pro-inflammatory cytokines, which may promote pulmonary emphysema and inflammation. The synergy between IL-18 and IL-12 involves infiltration of T-cells in the lungs, possibly induced by the T-cell chemoattractant CXCL9.

We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase (Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.