Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Graft quality before transplantation is a major factor influencing chronic rejection. Organ preservation and ischemia/reperfusion play an important role in the induction of organ injury. Although both suppression of metabolism by hypothermic preservation and preconditioning before ischemia limit injury, understanding the biochemical signaling pathways will allow us to optimize graft preservation further. Adenosine monophosphate-activated protein kinase (AMPK) is an important enzyme sensing cellular energy balance and regulating downstream signaling pathways, signaling toward an energy-conserving state. In this review, we summarize available literature regarding the protective signaling pathways activated by (hypothermic) ischemia and preconditioning and how they can be activated pharmacologically. Optimizing the graft quality before transplantation improves long-term graft survival. The major factor influencing organ quality is organ preservation, cold storage, currently, being a common practice. Loss of cellular homeostasis, inflammation, and endothelial dysfunction are the major factors inducing injury after cold storage. Adenosine triphosphate depletion and anaerobic metabolism during the cold ischemic period lead to mitochondrial dysfunction, disturbed osmoregulation, and cell death inducing inflammation. Ischemic preconditioning consists of brief periods of ischemia preceding preservation and protects organs against injury because of subsequent ischemia/reperfusion, in which endothelial nitric oxide synthase, nuclear factor-kB, and adenosine play a major role. After conversion of adenosine to AMP, AMPK can be activated, a central kinase involved in sensing cellular [AMP]:[adenosine triphosphate] levels and signaling toward an energy-conserving state. Pharmacologic activation of AMPK demonstrated its ability to activate endothelial nitric oxide synthase and inhibit nuclear factor-kB, thereby limiting endothelial dysfunction and inflammation. Further, studies in knock-out mice lacking ENTDP1 and NT5E (enzymes catalyzing formation and degradation of AMP, respectively) demonstrated a clear protective role for AMP in ischemia/reperfusion. AMPK activation before or during organ preservation might be a promising pharmacologic approach to limit organ injury and maintain graft quality before transplantation.
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PMID:AMP-activated protein kinase as a target for preconditioning in transplantation medicine. 2111 5

ACDC (arterial calcification due to deficiency of CD73) is an autosomal recessive disease resulting from loss-of-function mutations in NT5E, which encodes CD73, a 5'-ectonucleotidase that converts extracellular adenosine monophosphate to adenosine. ACDC patients display progressive calcification of lower extremity arteries, causing limb ischemia. Tissue-nonspecific alkaline phosphatase (TNAP), which converts pyrophosphate (PPi) to inorganic phosphate (Pi), and extracellular purine metabolism play important roles in other inherited forms of vascular calcification. Compared to cells from healthy subjects, induced pluripotent stem cell-derived mesenchymal stromal cells (iMSCs) from ACDC patients displayed accelerated calcification and increased TNAP activity when cultured under conditions that promote osteogenesis. TNAP activity generated adenosine in iMSCs derived from ACDC patients but not in iMSCs from control subjects, which have CD73. In response to osteogenic stimulation, ACDC patient-derived iMSCs had decreased amounts of the TNAP substrate PPi, an inhibitor of extracellular matrix calcification, and exhibited increased activation of AKT, mechanistic target of rapamycin (mTOR), and the 70-kDa ribosomal protein S6 kinase (p70S6K), a pathway that promotes calcification. In vivo, teratomas derived from ACDC patient cells showed extensive calcification and increased TNAP activity. Treating mice bearing these teratomas with an A2b adenosine receptor agonist, the mTOR inhibitor rapamycin, or the bisphosphonate etidronate reduced calcification. These results show that an increase of TNAP activity in ACDC contributes to ectopic calcification by disrupting the extracellular balance of PPi and Pi and identify potential therapeutic targets for ACDC.
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PMID:Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. 2796 23

CD73, also known as ecto-5'-nucleotidase (eN, NT5E, EC3.13.5), is the ratelimiting enzyme for adenosine generation and is expressed on multiple cells. Its expression is significantly influenced by hypoxia and inflammatory factors. During inflammation, CD73 protects endothelial barrier function and inhibits leukocyte trafficking. CD73 also promotes M2 macrophages (anti-inflammatory phenotype). In addition, CD73 is expressed on Treg cells and mediates immune suppression through adenosine. CD73 serves as an essential regulator for the immunity and inflammation. Its expression is related to many diseases, such as autoimmune diseases, ischemia-reperfusion injuries, arterial calcifications, and atherosclerosis. CD73 is overexpressed in many cancers. Its expression is positively associated with tumor growth, metastasis, angiogenesis, poor prognosis and resistance to chemotherapy. Thus, CD73 may be used for prognostic indicator and therapeutic target in diseases such as cancers.
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PMID:Role of CD73 in Disease: Promising Prognostic Indicator and Therapeutic Target. 2934 74

Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.
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PMID:Genetic variants in cardiac calcification in Northern Sweden. 3098 56

Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. Anti-CD73 inhibitory antibodies are currently undergoing clinical testing for cancer immunotherapy. However, many protective physiological functions of CD73 need to be taken into account for new targeted therapies. This review examines CD73 functions in multiple organ systems and cell types, with a particular focus on novel findings from the last 5 years. Missense loss-of-function mutations in the CD73-encoding gene NT5E cause the rare disease "arterial calcifications due to deficiency of CD73." Aside from direct human disease involvement, cellular and animal model studies have revealed key functions of CD73 in tissue homeostasis and pathology across multiple organ systems. In the context of the central nervous system, CD73 is antinociceptive and protects against inflammatory damage, while also contributing to age-dependent decline in cortical plasticity. CD73 preserves barrier function in multiple tissues, a role that is most evident in the respiratory system, where it inhibits endothelial permeability in an adenosine-dependent manner. CD73 has important cardioprotective functions during myocardial infarction and heart failure. Under ischemia-reperfusion injury conditions, rapid and sustained induction of CD73 confers protection in the liver and kidney. In some cases, the mechanism by which CD73 mediates tissue injury is less clear. For example, CD73 has a promoting role in liver fibrosis but is protective in lung fibrosis. Future studies that integrate CD73 regulation and function at the cellular level with physiological responses will improve its utility as a disease target.
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PMID:Cell type- and tissue-specific functions of ecto-5'-nucleotidase (CD73). 3146 41