1 Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom; 2 Division of Cardiology, School of Medicine, Université catholique de ...Louvain, Brussels, Belgium; 3 Maternal and Child Health Sciences, Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom; 4 The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom; and 5 Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
Submitted 13 September 2005
; accepted in final form 29 November 2005
Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPK 1/ 2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPK 2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPK 2 at the site of LKB1 phosphorylation (Thr 172 ) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPK 2, significant basal activity of AMPK 1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPK 1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPK 2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPK 1 in cardiac muscle.
cellular energy metabolism; hypoxia; cardiovascular physiology; AMP-activated protein kinase
Address for reprint requests and other correspondence: K. Sakamoto, Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, Univ. of Dundee, Dow St., Dundee DD1 5EH, UK (e-mail: k.sakamoto{at}dundee.ac.uk )
In this study, we have investigated the effect of altered corticosteroid levels on the expression and processing of the amyloid β precursor protein (A
βPP) and its amyloid precursor-like protein ...(APLP) homologue in rat brain. Four groups of animals were used in the study: sham operated, adrenalectomised, and adrenalectomised treated with either dexamethasone or aldosterone, with the AβPP/APLP expression being determined by western blot analysis. While there were no changes in the levels of AβPP/APLP following adrenalectomy, treatment with dexamethasone, but not aldosterone, resulted in a marked increase in protein expression levels with the level of increase varying between the brain regions examined. Corticosteroids had a more marked effect on the particulate rather than the soluble form of the protein, thus suggesting that elevated glucocorticoids may also be adversely influencing AβPP/APLP processing.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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