Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

I(f), a diastolic depolarizing current activated by hyperpolarization, is a key player in cardiac pacing. Despite the fact that I(f) has been known for over 20 years, the encoding genes, namely HCN1 to 4, have only recently been identified. Functional data imply that different HCN isoforms may coassemble to form heteromeric channel complexes, but little direct evidence is available. Subunit stoichiometry is also unknown. Although the pore region of HCN channels contains the glycine-tyrosine-glycine (GYG) signature motif found in K+-selective channels, they permeate both Na+ and K+. In the present study, we probed the functional importance of the GYG selectivity motif in pacemaker channels by replacing this triplet in HCN1 with alanines (GYG(349-351)AAA or HCN1-AAA). HCN1-AAA did not yield functional currents; coexpression of HCN1-AAA with wild-type (WT) HCN1 suppressed normal channel activity in a dominant-negative manner (55.2+/-3.2%, 68.3+/-4.3%, 78.7+/-1.6%, 91.7+/-0.8%, and 97.9+/-0.2% current reduction at -140 mV for WT:AAA cRNA ratios of 4:1, 3:1, 2:1, 1:1, and 1:2, respectively) without affecting gating (steady-state activation, activation and deactivation kinetics) or permeation (reversal potential) properties. HCN1-AAA coexpression, however, did not alter the expressed current amplitudes of Kv1.4 and Kv2.1 channels, indicating that its suppressive effect was channel-specific. Statistical analysis reveals that a single HCN channel is composed of 4 monomeric subunits. Interestingly, HCN1-AAA also inhibited HCN2 in a dominant-negative manner with the same efficacy. We conclude that the GYG motif is a critical determinant of ion permeation for HCN channels, and that HCN1 and HCN2 readily coassemble to form heterotetrameric complexes.
 ...
PMID:Dominant-negative suppression of HCN1- and HCN2-encoded pacemaker currents by an engineered HCN1 construct: insights into structure-function relationships and multimerization. 1208 64

Human abdominal aortic aneurysm (AAA) is characterized by the induction of intracellular and extracellular inflammatory cytokines and the production of reactive oxygen species (ROS) associated with localized inflammatory responses in the vascular wall. Recent studies have shown that greater circulating levels of the proinflammatory cytokine interleukin-6 (IL-6) are closely associated with AAA presence, suggesting that IL-6 plays an important role in the development of AAA. Previous in vivo studies have indicated that excess activities of NADPH oxidase (NOX), a major oxidase system for ROS production, promote AAA development. Furthermore, long noncoding RNAs (lncRNAs) are involved in the development of AAA. LncRNA MALAT1 has been found closely involved in endothelial cell functions and dysfunctions. In the present study, we explored the effects and the underlying mechanisms of IL-6 and MALAT1 on the expression/activity of NOXs in human aortic endothelial cells (HAOECs). Primary HAOECs with or without overexpression or knockdown of MALTA1 were cultured in the presence of IL-6. We found that IL-6 concentration- and time-dependently elevated the NOX activity as well as the MALAT1 level in HAOECs. Among different NOXs, only NOX2 was induced by IL-6. Overexpression and knockdown of MALAT1 respectively augmented and abolished IL6-induced expression of NOX2, NOX activity/cellular ROS production, and activation of the human NOX2 gene promoter, whereas MALAT1 alone in the absence of IL-6 treatment showed no significant effect. Knockdown of extracellular signal-regulated kinase (ERK) abolished IL6-induced expression of MALAT1. In conclusion, this study provides the first evidence that IL-6 induces expression/activity of NOX2 in HAOECs via inducing MALAT1 by an ERK-dependent mechanism. It adds new insights into the molecular mechanisms underlying AAA development.
 ...
PMID:Interleukin 6 induces expression of NADPH oxidase 2 in human aortic endothelial cells via long noncoding RNA MALAT1. 2944 28