a-novel-inhalation-mask-system-to-deliver-high-concentrations-nitric

A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects

Nitric Oxide (NO) is administered as gas for inhalation to induce selective pulmonary vasodilation. It is a safe therapy, with few potential risks even if ...

Massachusetts General Hospital and Harvard Medical School

The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 are essential for expression of hepcidin, a key iron regulatory hormone. In mice, hepatocyte-specific Alk2 deficiency leads to moderate iron overload with periportal liver iron accumulation, while hepatocyte-specific Alk3 deficiency leads to severe iron overload with centrilobular liver iron accumulation and a more marked reduction of basal hepcidin levels. The objective of this study was to investigate whether the two receptors have additive roles in hepcidin regulation. Iron overload in mice with hepatocyte-specific Alk2 and Alk3 (Alk2/3) deficiency was characterized and compared to hepatocyte-specific Alk3 deficient mice. Co-immunoprecipitation studies were performed to detect the formation of ALK2 and ALK3 homodimer and heterodimer complexes in vitro in the presence and absence of ligands. The iron overload phenotype of hepatocyte-specific Alk2/3-deficient mice was more severe than that of hepatocyte-specific Alk3-deficient mice. In vitro co-immunoprecipitation studies in Huh7 cells showed that ALK3 can homodimerize in absence of BMP2 or BMP6. In contrast, ALK2 did not homodimerize in either the presence or absence of BMP ligands. However, ALK2 did form heterodimers with ALK3 in the presence of BMP2 or BMP6. ALK3-ALK3 and ALK2-ALK3 receptor complexes induced hepcidin expression in Huh7 cells. Our data indicate that: (I) ALK2 and ALK3 have additive functions in vivo, as Alk2/3 deficiency leads to a greater degree of iron overload than Alk3 deficiency; (II) ALK3, but not ALK2, undergoes ligand-independent homodimerization; (III) the formation of ALK2-ALK3 heterodimers is ligand-dependent and (IV) both receptor complexes functionally induce hepcidin expression in vitro.

ALK3 undergoes ligand-independent homodimerization and BMP-induced heterodimerization with ALK2.

Atherosclerotic cardiovascular disease is a major burden on global health and a leading cause of death worldwide. The pathophysiology of this chronic disease is complex, involving inflammation, lipoprotein oxidation and accumulation, plaque formation, and calcification. In 1981, Dr. Jerome Sullivan formulated the 'Iron Hypothesis', suggesting that higher levels of stored iron promote cardiovascular diseases, whereas iron deficiency may have an atheroprotective effect. This hypothesis has stimulated research focused on clarifying the role of iron in the development of atherosclerosis. However, preclinical and clinical studies have produced contradictory results and the observation that patients with hemochromatosis do not appear to have an increased risk of atherosclerosis seemed incongruous with Sullivan's initial hypothesis. The 'paradox' of systemic iron overload not being accompanied by an increased risk for atherosclerosis led to a refinement of the iron hypothesis focusing on intracellular macrophage iron. More recent in vitro and animal studies have elucidated the complex signaling pathways regulating iron, with a particular focus on hepcidin, the master regulator of body iron homeostasis. Bone morphogenetic protein (BMP) signaling is the major pathway that is required for induction of hepcidin expression in response to increasing levels of iron. Strong links between iron homeostasis, BMP signaling, inflammation and atherosclerosis have been established in both mechanistic and human studies. This review summarizes the current understanding of the role of iron homeostasis and hepcidin in the development of atherosclerosis and discusses the BMP-hepcidin-ferroportin axis as a novel therapeutic target for the treatment of cardiovascular disease.

The role of hepcidin and iron homeostasis in atherosclerosis.

Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe/hepatic Alk3;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3;Alb-Cre mice compared to Alk3 mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.

Lisa Traeger

Department of Anesthesia,
Critical Care and Pain Medicine,
Department of Anesthesia, Critical Care and Pain Medicine

Massachusetts General Hospital and Harvard Medical School

A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects

Lisa Traeger

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Anesthesia,Critical Care and Pain Medicine,Department of Anesthesia, Critical Care and Pain Medicine

Massachusetts General Hospital and Harvard Medical School

A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects

Department of Anesthesia,
Critical Care and Pain Medicine,
Department of Anesthesia, Critical Care and Pain Medicine