Article

AMPK isoform expression in the normal and failing hearts

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.22). 01/2012; 52(5):1066-73. DOI: 10.1016/j.yjmcc.2012.01.016
Source: PubMed

ABSTRACT AMP-activated protein kinase (AMPK) is a master metabolic switch that plays an important role in energy homeostasis at the cellular and whole body level, hence a promising drug target. AMPK is a heterotrimeric complex composed of catalytic α-subunit and regulatory β- and γ-subunits with multiple isoforms for each subunit. It has been shown that AMPK activity is increased in cardiac hypertrophy and failure but it is unknown whether changes in subunit composition of AMPK contribute to the altered AMPK activity. In this study, we determined the protein expression pattern of AMPK subunit isoforms during cardiac development as well as during cardiac hypertrophy and heart failure in mouse heart. We also compared the findings in failing mouse heart to that of the human failing hearts in order to determine whether the mouse heart is a good model of AMPK in human diseases. In mouse developmental hearts, AMPK was highly expressed in the fetal stages and fell back to the adult level after birth. In the failing mouse heart, there was a significant increase in α2, β2, and γ2 subunits both at the mRNA and protein levels. In contrary, we found significant increases in the protein level of α1, β1 and γ2c subunits in human failing hearts with no change in the mRNA level. We also compared isoform-specific AMPK activity in the mouse and human failing hearts. Consistent with the literature, in the failing mouse heart, the α2 complexes accounted for ~2/3 of total AMPK activity while the α1 complexes accounted for the remaining 30-35%. In the human hearts, however, the contribution of α1-AMPK activity was significantly higher (>40%) in the non-failing hearts, and it further increased to 50% in the failing hearts. Thus, the human hearts have a greater amount of α1-AMPK activity compared to the rodent hearts. In summary, the protein level and the isoform distribution of AMPK in the heart change significantly during normal development as well as in heart failure. These observations provide a basis for future development of therapeutic strategies for targeting AMPK.

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    • "Activation of AMPK has been reported in numerous rodent models of cardiac injury (including pressure overload , hypoxia and ischemia) as an adaptive response and was associated with enhanced glucose uptake (Huang et al. 2014; Nishino et al. 2004; Tian et al. 2001). Elevated AMPK protein expression and activity have been demonstrated in human failing hearts, although AMPK expression has not been extensively studied in all forms of HF (Kim et al. 2012). Pharmacological activation of AMPK has been shown to inhibit the mTOR pathway and attenuate pressure overload-induced hypertrophy (Chan et al. 2004, 2008; Li et al. 2007). "
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