Role of acadesine in clinical myocardial protection.

Alkhulaifi, Abdulaziz; Pugsley, W

doi:10.1136/hrt.73.4.304

Cited by 10 publications

(7 citation statements)

References 21 publications

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“…Previous studies have provided evidence that AICAR protects against I/R injury in several tissues, such as heart and liver (Bullough et al ., 1994; Alkhulaifi and Pugsley, 1995; Galinanes et al ., 1995; Mathew et al ., 1995; Peralta et al ., 2001). Lin et al .…”

Section: Discussionmentioning

confidence: 99%

AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

Lempiäinen

Finckenberg

Levijoki

et al. 2012

British J Pharmacology

105

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BACKGROUND AND PURPOSE Renal ischaemia/reperfusion (RI/R) injury is a major cause of acute kidney injury (AKI) and an important determinant of long‐term kidney dysfunction. AMP‐kinase and histone deacetylase sirtuin 1 (SIRT1) regulate cellular metabolism and are activated during hypoxia. We investigated whether AMP‐kinase activator AICAR (5‐amino‐4‐imidazolecarboxamide riboside‐1‐β‐D‐ribofuranoside) ameliorates RI/R injury and whether SIRT1 is involved in the pathogenesis. EXPERIMENTAL APPROACH Eight‐week‐old Sprague Dawley rats were divided into five groups: (i) sham‐operated group; (ii) I/R group (40 min bilateral ischaemia followed by 24 h of reperfusion; (iii) I/R group + AICAR 50 mg·kg−1 i.v. given 60 min before operation; (iv). I/R group + AICAR 160 mg·kg−1 i.v; (v) I/R group + AICAR 500 mg·kg−1 i.v. Serum creatinine and urea levels were measured. Acute tubular necrosis (ATN), monocyte/macrophage infiltration and nitrotyrosine expression were scored. Kidney AMP‐activated protein kinase (AMPK) and SIRT1 expressions were measured. KEY RESULTS Highest dose of AICAR decreased serum creatinine and urea levels, attenuated I/R injury‐induced nitrosative stress and monocyte/macrophage infiltration, and ameliorated the development of ATN. Kidney I/R injury was associated with decreased AMPK phosphorylation and a fivefold increase in kidney SIRT1 expression. AICAR increased pAMPK/AMPK ratio and prevented the I/R‐induced increase in renal SIRT1 expression. CONCLUSIONS AND IMPLICATIONS AICAR protects against the development of ATN after kidney I/R injury. Activators of kidney AMP kinase may thus represent a novel therapeutic approach to patients susceptible to AKI and to those undergoing kidney transplantation. The present study also suggests a role for SIRT1 in the pathogenesis of RI/R injury.

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Section: Discussionmentioning

confidence: 99%

AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

Lempiäinen

Finckenberg

Levijoki

et al. 2012

British J Pharmacology

105

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“…Based on the fact that AMPK activation is part of the cellular response to stress (14), and based on the suggestion that such activation can protect against organ injury by decreasing inflammation in multiple animal models including hemorrhagic shock, ischemic preconditioning and ischemia/reperfusion (3, 15–21), these experiments were designed to test the hypothesis that AMPK protects against sepsis induced endothelial activation and injury, and that AMPK agonists would limit organ injury and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation

Escobar

Botero-Quintero

Kautza

et al. 2015

Journal of Surgical Research

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Background Mortality in sepsis is most often attributed to the development of multiple organ failure. In sepsis, inflammation-mediated endothelial activation, defined as a proinflammatory and procoagulant state of the endothelial cells, has been associated with severity of disease. Thus, the objective of this study was to test the hypothesis that AMPK activation limits inflammation and endothelium activation to protect against organ injury in sepsis. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is an AMP analogue, has been used to upregulate activity of AMPK. Compound C is a cell-permeable pyrrazolopyrimidine compound that inhibits AMPK activity. Methods Wild-type mice underwent CLP or Sham surgery. Mice were randomized to vehicle, AICAR, or Compound C. Mouse kidney endothelial cells were used for in vitro experiments. Renal and liver function, were determined by serum Cystatin C, BUN, creatinine, and ALT. Serum cytokines were measured by ELISA. Microvascular injury was determined using Evan’s blue dye and electron microscopy. Immunohistochemistry was used to measure protein levels of p-AMPK, LC3, and ICAM. LC3 levels were used as a measure of autophagosome formation. Results AICAR decreased liver, and kidney injury induced by CLP and minimized cytokine elevation, in vivo and in vitro. CLP increased renal and hepatic phosphorylation of AMPK and autophagic signaling as determined by LC3. Inhibition of AMPK with Compound C prevented CLP-induced autophagy and exacerbated tissue injury. Additionally, CLP led to endothelial injury as determined by electron microscopy and Evan’s blue dye extravasation, and AICAR limited this injury. Furthermore, AICAR limited CLP and LPS induced upregulation of ICAM in vivo and in vitro, and decreased LPS induced neutrophil adhesion in vitro. Conclusion In this model, activation of AMPK was protective and AICAR minimized organ injury by decreasing inflammatory cytokines and endothelial activation. These data suggest that AMPK signaling influences sepsis or LPS induced endothelial activation and organ injury.

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“…237,238 Acadesine, a synthetic adenosine regulator, has been shown to increase the availability of adenosine in ischemic tissues undergoing ATP depletion, and has, therefore, been implicated as a potential myocardial pharmacologic preconditioning agent. 239,240 Nicorandil, an agonist of KATP channels that reduces angina, has shown promising results when given as an adjunct to cardioplegia. It appears to decrease the need for use of high-dose inotropic agents after cardiac surgery and increases ischemic tolerance in humans during PTCA.…”

Section: Pharmacologic Preconditioningmentioning

confidence: 99%

Hibernation, Stunning, and Preconditioning: Historical Perspective, Current Concepts, Clinical Applications, and Future Implications

Cosar¹,

O’Connor

2003

Semin Cardiothorac Vasc Anesth

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Despite considerable advances, coronary artery disease is the leading cause of morbidity and mortality in the Western world. The development of effective therapeutic strategies for protecting the myocardium from ischemia would have major impact on patients with coronary artery disease. It is now accepted that patients with coronary artery disease can experience prolonged regional ischemic dysfunction that does not necessarily arise from irreversible tissue damage, and to some extent, can be reversed by restoration of blood flow. The initial stages of dysfunction are probably caused by chronic stunning that can be reversed after revascularization, resulting in rapid and complete functional recovery. On the other hand, the more advanced stages of dysfunction likely correspond to chronic hibernation. After revascularization, functional recovery will probably be quite delayed and mostly incomplete. Over the past decade, the possibility that an innate mechanism of myocardial protection might be inducible in the human heart has generated considerable excitement. In the last two decades, there was phenomenal growth in the understanding of the mechanism known as ischemic preconditioning that is responsible for the innate myocardial protection. Continued research and progress in this area may soon lead to the availability of preconditioning-mimetic treatments. The current concepts, mechanisms, and potential clinical applications of myocardial hibernation, stunning, and ischemic preconditioning are reviewed. M yocardial infarction continues to be among the most frequent causes of debilitating illness and death. Tissue damage from myocardial infarction occurs as a result of the initial ischemic event, primarily determined by its duration, and the subsequent injury resulting from reperfusion.In the past 15 years, understanding of the pathophysiologic processes involved in chronic and From the

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Role of acadesine in clinical myocardial protection.

Abstract: Acadesine (AICA riboside, 5-amino-1-,fl-D-ribofuranosyl-imidazole-4-carboxamide) is the prototype of a new class of compounds termed adenosine regulating agents. Acadesine is a purine nucleoside analogue that enters the myocyte and is immediately phosphorylated to ZMP

Cited by 10 publications

References 21 publications

AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney

Adenosine monophosphate-activated protein kinase activation protects against sepsis-induced organ injury and inflammation

Hibernation, Stunning, and Preconditioning: Historical Perspective, Current Concepts, Clinical Applications, and Future Implications

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