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...
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.
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