Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting

Newman, Mark F.; Ferguson, T. Bruce; White, Jennifer A.; Ambrosio, Giuseppe; Koglin, Joerg; Nussmeier, Nancy A.; Pearl, Ronald G.; Pitt, Bertram; Wechsler, Andrew S.; Weisel, Richard D.; Reece, Tammy; Lira, Armando; Harrington, Robert A.; Investigators,

doi:10.1001/jama.2012.7633

Cited by 42 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On this last note we have not observed adverse effects from AICAR treatment of aged mice in this study nor in our previous studies [10]. AICAR has also been used clinically with no severe adverse effects [15]. …”

Section: Discussionsupporting

confidence: 56%

Aicar treatment reduces interstitial fibrosis in aging mice

Cieslik

Trial

Entman

2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

In 2030, elderly people will represent 20% of the United States population. Even now, chronic cardiac diseases, especially heart failure with preserved systolic function (HFpEF), are the most expensive DRGs for Medicare. Progressive interstitial fibrosis in the aging heart is well recognized as an important component of HFpEF. Our recent studies suggested an important pathophysiologic role for reduced TGF-β receptor 1 (TGFβR1) signaling in mesenchymal stem cells (MSCs) and their mesenchymal fibroblast progeny in the development of interstitial fibrosis. This report arises from our previous studies, which suggest that an inflammatory phenotype exists in these mesenchymal fibroblasts as a result of a reduced TGF-β-Smad-dependent pathway but upregulated farnesyltransferase (FTase)-Ras-Erk signaling. In this report we provide evidence for a therapeutic approach that downregulates Erk activation through an adenosine monophosphate-activated kinase (AMPK) pathway. Aging C57BL/6J mice were treated with AICAR (an AMPK activator) for a 30-day period. This treatment suppressed excessive monocyte chemoattractant protein-1 (MCP-1) generation, which diminished leukocyte infiltration and in consequence suppressed the formation of macrophage-derived myeloid fibroblasts. Interestingly, the number of mesenchymal fibroblasts was also reduced. In addition, we observed changes in extracellular matrix (ECM) deposition, specifically that collagen type I and the alternatively spliced variant of fibronectin (EDA) expressions were reduced. These data suggest that the upregulation of AMPK activity is a potential therapeutic approach to fibrosis in the aging heart.

show abstract

Section: Discussionsupporting

confidence: 56%

Aicar treatment reduces interstitial fibrosis in aging mice

Cieslik

Trial

Entman

2017

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…Deletion of the PKCα gene 222285 or inhibition with drugs 286287135 have shown dramatic protective effects against the development of heart failure of various etiologies including ischemia, pressure overload or dilated cardiomyopathy induced by deleting LIM protein in animal models. However, clinical trials with PKC inhibitors or RACK inhibitor peptides were largely disappointing for improving heart failure 288 or reducing myocardial injury in MI patients 289290 .…”

Section: Therapeutic Targets For Heart Failurementioning

confidence: 99%

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Luo

Anderson

2013

Circulation Research

319

250

View full text Add to dashboard Cite

Ca2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca2+ homeostatic binding proteins, ion channels and enzymes. This review focuses on the molecular mechanisms of defective Ca2+ cycling in heart failure and consider how fundamental understanding of these pathways may translate into novel and innovative therapies.

show abstract

“…In the 1980s and 1990s, AICAR was under development as an agent that would reduce cardiac injury associated with coronary artery bypass grafting. Although initial trials clearly demonstrated success, later trials showed a minimal efficacy as the morbidity and mortality rates associated with the procedure decreased dramatically owing to better techniques and increased familiarity with the procedures (35,36). When added to cultured cells or administered into animals or humans, AICAR is phosphorylated to become AICA-ribotide (ZMP), the natural endogenous intermediate in de novo purine nucleotide biosynthesis, which can function as an AMP mimic and can activate AMPK.…”

Section: Discussionmentioning

confidence: 99%

AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway

Morishita

Kawamoto

Hara

et al. 2016

International Journal of Oncology

View full text Add to dashboard Cite

The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) modulates cellular energy metabolism, and promotes mitochondrial proliferation and apoptosis. Previous studies have shown that AICAR has anticancer effects in various cancers, however the roles of AMPK and/or the effects of AICAR on osteosarcoma have not been reported. In the present study, we evaluated the effects of AICAR on tumor growth and mitochondrial apoptosis in human osteosarcoma both in vitro and in vivo. For in vitro experiments, two human osteosarcoma cell lines, MG63 and KHOS, were treated with AICAR, and the effects of AICAR on cell growth and mitochondrial apoptosis were assessed by WST assays, TUNEL staining, and immunoblot analyses. In vivo, human osteosarcoma-bearing mice were treated with AICAR, and the mitochondrial proliferation and apoptotic activity in treated tumors were assessed. In vitro experiments revealed that AICAR activated AMPK, inhibited cell growth, and induced mitochondrial apoptosis in both osteosarcoma cell lines. In vivo, AICAR significantly reduced osteosarcoma growth without apparent body weight loss and AICAR increased both mitochondrial proliferation and apoptotic activity in treated tumor tissues. AICAR showed anticancer effects in osteosarcoma cells through an AMPK-dependent peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/mitochondrial transcription factor A (TFAM)/mitochondrial pathway. The findings in this study strongly suggest that AICAR could be considered as a potent therapeutic agent for the treatment of human osteosarcoma.

show abstract

Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting

Cited by 42 publications

References 34 publications

Aicar treatment reduces interstitial fibrosis in aging mice

Aicar treatment reduces interstitial fibrosis in aging mice

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway

Contact Info

Product

Resources

About

Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting

Cited by 42 publications

References 34 publications

Aicar treatment reduces interstitial fibrosis in aging mice

Aicar treatment reduces interstitial fibrosis in aging mice

Mechanisms of Altered Ca 2+ Handling in Heart Failure

AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway

Contact Info

Product

Resources

About

Mechanisms of Altered Ca ²⁺ Handling in Heart Failure