Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In skeletal muscle, excitation may cause loss of K+, increased extracellular K+ ([K+]o), intracellular Na+ ([Na+]i), and depolarization. Since these events interfere with excitability, the processes of excitation can be self-limiting. During work, therefore, the impending loss of excitability has to be counterbalanced by prompt restoration of Na+-K+ gradients. Since this is the major function of the Na+-K+ pumps, it is crucial that their activity and capacity are adequate. This is achieved in two ways: 1) by acute activation of the Na+-K+ pumps and 2) by long-term regulation of Na+-K+ pump content or capacity. 1) Depending on frequency of stimulation, excitation may activate up to all of the Na+-K+ pumps available within 10 s, causing up to 22-fold increase in Na+ efflux. Activation of the Na+-K+ pumps by hormones is slower and less pronounced. When muscles are inhibited by high [K+]o or low [Na+]o, acute hormone- or excitation-induced activation of the Na+-K+ pumps can restore excitability and contractile force in 10-20 min. Conversely, inhibition of the Na+-K+ pumps by ouabain leads to progressive loss of contractility and endurance. 2) Na+-K+ pump content is upregulated by training, thyroid hormones, insulin, glucocorticoids, and K+ overload. Downregulation is seen during immobilization, K+ deficiency, hypoxia, heart failure, hypothyroidism, starvation, diabetes, alcoholism, myotonic dystrophy, and McArdle disease. Reduced Na+-K+ pump content leads to loss of contractility and endurance, possibly contributing to the fatigue associated with several of these conditions. Increasing excitation-induced Na+ influx by augmenting the open-time or the content of Na+ channels reduces contractile endurance. Excitability and contractility depend on the ratio between passive Na+-K+ leaks and Na+-K+ pump activity, the passive leaks often playing a dominant role. The Na+-K+ pump is a central target for regulation of Na+-K+ distribution and excitability, essential for second-to-second ongoing maintenance of excitability during work.
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PMID:Na+-K+ pump regulation and skeletal muscle contractility. 1450 6

Excitability is a fundamental characteristic of cardiac cells, which is delicately determined by ion channel activities modulated by many factors. MicroRNA (miRNA) expression is dynamically regulated and altered miRNA expression can render expression deregulation of ion channel genes leading to channelopathies-arrhythmogenesis. Indeed, evidence has emerged indicating the crucial role of miRNAs in controlling cardiac excitability by regulating expression of ion channel genes at the post-transcriptional level. However, the very limited experimental data in the literature hinder our understanding of the role of miRNAs and the often one-to-one interaction between miRNA and ion-channel gene in the published studies also casts a doubt about fullness of our view. Unfortunately, currently available techniques do not permit thorough characterization of miRNA targeting; computational prediction programs remain the only source for rapid identification of a putative miRNA target in silico. We conducted a rationally designed bioinformatics analysis in conjunction with experimental approaches to identify the miRNAs from the currently available miRNA databases which have the potential to regulate human cardiac ion channel genes and to validate the analysis with several pathological settings associated with the deregulated miRNAs and ion channel genes in the heart. We established a matrix of miRNAs that are expressed in cardiac cells and have the potential to regulate the genes encoding cardiac ion channels and transporters. We were able to explain a particular ionic remodeling process in hypertrophy/heart failure, myocardial ischemia, or atrial fibrillation with the corresponding deregulated miRNAs under that pathological condition; the changes of miRNAs appear to have anti-correlation with the changes of many of the genes encoding cardiac ion channels under these situations. These results indicate that multiple miRNAs might be critically involved in the electrical/ionic remodeling processes of cardiac diseases through altering their expression in cardiac cells, which has not been uncovered by previous experimental studies.
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PMID:Regulation of human cardiac ion channel genes by microRNAs: theoretical perspective and pathophysiological implications. 2051 2