Common Variant in
            <i>AMPD1</i>
            Gene Predicts Improved Clinical Outcome in Patients With Heart Failure

Loh, Evan; Rebbeck, Timothy R.; Mahoney, Paul; DeNofrio, David; Swain, Judith L.; Holmes, Edward W.

doi:10.1161/01.cir.99.11.1422

Cited by 125 publications

(83 citation statements)

References 26 publications

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“…Since the decrease in adenosine deaminase activity contributes to the increase in adenosine production, which is believed to be cardioprotective, these changes are thought to compensate for the downregulation of adenosine receptors and the pathophysiology of CHF. Furthermore, the present study may be consistent with the report by Loh et al (9) showing that CHF patients with the AMP deaminase mutation, whose plasma adenosine levels are increased because of inability to deaminase AMP, have a better prognosis than patients without that mutation.…”

supporting

confidence: 93%

Adenosine and Cardioprotection in Chronic Heart Failure: Genes and Protein Expression

Hisatome¹

2007

Hypertens Res

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Adenosine, a natural metabolic autacoid, ubiquitously exists inside or outside of all living cells. It plays multiple physiological roles to maintain the homeostasis of cells and thus of tissues and organs including the heart. Adenosine is released from cells and interacts with specific cell membrane receptors to modulate cell function in an autocrine or paracrine manner (1-3). The events modulated via adenosine receptors include decreases in heart rate, contractility, and smooth muscle tone; the induction of sedation; the release of neurotransmitters; and the promotion of glycolysis and lipolysis as well as the modulation of renal, platelet, leukocyte, and endothelial cellular functions. In cardiovascular systems, adenosine mediates the negative chronotropic actions on the sinus node and the atrioventricular node (1). Its direct negative chronotropic and dromotropic properties are the basis for its wide diagnostic and therapeutic application in patients with supraventricular tachycardia (4, 5). On the other hand, several lines of evidence suggest that adenosine is cardioprotective in patients with congestive heart failure (CHF) and ischemic heart disease (6, 7), since adenosine is believed to be cardioprotective against CHF via 1) the attenuation of catecholamine release, β-adrenoreceptor-mediated myocardial hypercontraction, and myocardial Ca 2+ overload; 2) the increases in coronary blood flow; and 3) the inhibition of platelet and leukocyte activation.Adenosine is produced from AMP via dephosphorylation by 5′-nucleotidase located in the cytosol of the cardiac cells, together with the significant contribution of its formation from S-adenosyl homocystine (SAH) by SAH hydrolase.Adenosine is degraded by adenosine deaminase and adenosine kinase. Adenosine interacts with A1, A2a, A2b and A3 receptors. However, the modulation of adenosine receptors and the degradation of endogenous adenosine in CHF are not fully understood.The intriguing and timely article by Asakura et al. in the present issue of Hypertension Research (8) provides new evidence that impairment of adenosine-related systems significantly contributes to the pathophysiology of CHF. They show that the gene expressions of adenosine A1, A2a, A2b, and A3 receptors, adenosine deaminase, and cytosolic 5′-nucleotidase were decreased in human failing myocardium, while those of adenosine receptor, adenosine kinase, and ecto 5′-nucleotidase were no different than those in nonfailing myocardium. In accordance with the impaired gene expression of adenosine deaminase, its enzyme activity was also decreased with the higher cardiac adenosine levels in CHF patients with New York Heart Assciation (NYHA) II-III than in patients with NYHA I. This finding may throw a brilliant light on the adenosine's role in the pathophysiology of CHF, because this is the first study to show direct evidence that adenosine deaminase is related to CHF.What are the roles of the down-regulation of the gene expression of adenosine deaminase, and of the modulated activities of adenosine deamin...

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confidence: 93%

Adenosine and Cardioprotection in Chronic Heart Failure: Genes and Protein Expression

Hisatome¹

2007

Hypertens Res

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“…In this study, we found that the C34T polymorphism of the AMPD1 gene leads to increased SBP and DBP, while previous studies suggested that AMPD1 may have promising effects on cardiovascular diseases (Feldman et al, 1999;Loh et al, 1999;Anderson et al, 2000). SBP was significantly lower in the CC carriers, in contrast to the results reported by Safranow et al (2009).…”

Section: Discussioncontrasting

confidence: 60%

Association between the C34T polymorphism of the AMPD1 gene and essential hypertension in Malaysian patients

Nemati¹,

Lü²,

Ramachandran³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to determine whether C34T, a common polymorphism of the adenosine monophosphate deaminase 1 gene (AMPD1), is associated with essential hypertension (EH). We hypothesize that C34T is associated with the development of EH. A casecontrol design was used for this study. The DNA was extracted using a commercial kit from the whole blood of 200 patients with hypertension and 200 subjects without hypertension from selected Malaysian ethnicities (Malays, Chinese, and Indians). Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis were used for genotyping. The C34T gene polymorphism of AMPD1 was significantly associated with EH in the Malaysian subjects (P < 0.0001). The genotype frequencies of CC, CT, and TT were 6%, 79%, and 15%, respectively, among hypertensive subjects, while no TT genotypes were observed in the normotensive subjects. Further, the frequency of hypertension was higher among T allele carriers than C carriers (OD = 9.94; 95%CI = 6.851-14.434). There were significant differences in the systolic blood pressure, diastolic blood pressure, and pulse pressure (P ˂ 0.05) between the normotensive and hypertensive Malaysian subjects; we believe those difference were caused by the C34T polymorphism. For the first time in Malaysia, the current study provides evidence that a common polymorphism of the AMPD1 gene (C34T) is strongly associated with EH.

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“…In addition to an energetic function, AK has a distinct signaling role through generation of AMP and activation of AMPdependent processes (9,38,39), including opening of ATPsensitive potassium (K ATP ) channels (7) and adenosine production (40,41). This is of significance in view of the role that these AK-catalysis dependent events play in protecting the myocardium under hypoxic insult (37).…”

Section: Discussionmentioning

confidence: 99%

Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress

Pucar

Janssen

Dzeja

et al. 2000

Journal of Biological Chemistry

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Rapid exchange of high energy carrying molecules between intracellular compartments is essential in sustaining cellular energetic homeostasis. Adenylate kinase (AK)-catalyzed transfer of adenine nucleotide ␤-and ␥-phosphoryls has been implicated in intracellular energy communication and nucleotide metabolism. To demonstrate the significance of this reaction in cardiac energetics, phosphotransfer dynamics were determined by [18 O]phosphoryl oxygen analysis using 31 P NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AK activity and ␤-phosphoryl transfer was reduced by 94% and 36%, respectively. This was associated with up-regulation of phosphoryl flux through remaining minor AK isoforms and the glycolytic phosphotransfer enzyme, 3-phosphoglycerate kinase. In the absence of metabolic stress, deletion of AK1 did not translate into gross abnormalities in nucleotide levels, ␥-ATP turnover rate or creatine kinase-catalyzed phosphotransfer. However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased P i /ATP ratio, and suppressed generation of adenosine. Thus, although lack of AK1 phosphotransfer can be compensated in the absence of metabolic challenge, under hypoxia AK1-knockout hearts display compromised energetics and impaired cardioprotective signaling. This study, therefore, provides first direct evidence that AK1 is essential in maintaining myocardial energetic homeostasis, in particular under metabolic stress. Adenylate kinase (AK)1 catalyzes reversible phosphotransfer, 2 ADP 7 AMP ϩ ATP, and participates in de novo synthesis, regeneration and salvage of adenine nucleotides (1-5). AK is particularly abundant in tissues with high energy turnover, where it facilitates transfer of energy-rich ␤-and ␥-phosphoryls and regulates vital ATP-dependent cellular processes (6 -10).In fact, AK may serve as an integral component of phosphotransfer networks, along with creatine kinase (CK) and glycolysis, effectively coupling ATP-generating with ATP-consuming or ATP-sensing intracellular sites (11-15).In the heart, CK-catalyzed phosphotransfer is the major pathway that can transfer high energy phosphoryls derived from the ␥-phosphoryl of ATP (10, 16 -18). Although less active than CK, AK catalysis provides a unique mechanism for transfer and utilization of both ␥-and ␤-phosphoryls in the ATP molecule (10, 15). In this way, AK-catalyzed phosphotransfer doubles the energetic potential of ATP and could provide an additional energetic source under conditions of increased energy demand (10, 19). However, due to lack of membrane permeant and selective AK inhibitors, the biological importance of AK in heart muscle and its role in sustaining myocardial energetics under conditions of metabolic stress have not been established.We have recently demonstrated that deletion of the AK1 gene, which encodes the major AK isoform, produces a phenotype with reduced skelet...

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Common Variant in AMPD1 Gene Predicts Improved Clinical Outcome in Patients With Heart Failure

Cited by 125 publications

References 26 publications

Adenosine and Cardioprotection in Chronic Heart Failure: Genes and Protein Expression

Adenosine and Cardioprotection in Chronic Heart Failure: Genes and Protein Expression

Association between the C34T polymorphism of the AMPD1 gene and essential hypertension in Malaysian patients

Compromised Energetics in the Adenylate Kinase AK1Gene Knockout Heart under Metabolic Stress

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