AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Aaron K. F. Wong, Jacqueline Howie, John R. Petrie, Chim C. Lang

    Research output: Contribution to journalReview article

    118 Citations (Scopus)

    Abstract

    AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKBI and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

    Original languageEnglish
    Pages (from-to)607-620
    Number of pages14
    JournalClinical and Translational Science
    Volume116
    Issue number7-8
    DOIs
    Publication statusPublished - Apr 2009

    Keywords

    • 5-amino-4-imidazolecarboxamide riboside-1-beta-D-ribofuranoside (AICAR)
    • AMP-activated protein kinase (AMPK)
    • cardiovascular disease
    • insulin resistance
    • metformin
    • obesity
    • PARKINSON-WHITE-SYNDROME
    • ACETYL-COA CARBOXYLASE
    • NITRIC-OXIDE SYNTHESIS
    • ISCHEMIA-REPERFUSION INJURY
    • INSULIN-RESISTANCE SYNDROME
    • AORTIC ENDOTHELIAL-CELLS
    • CORONARY-ARTERY-DISEASE
    • COENZYME-A REDUCTASE
    • FATTY-ACID OXIDATION
    • IN-VIVO

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