The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
A small molecule AMPK activator protects the heart against ischemia–reperfusion injury
Open accessAbstract
AMP-activated protein kinase (AMPK) is a stress signaling enzyme that orchestrates the regulation of energy-generating and -consuming pathways. Intrinsic AMPK activation protects the heart against ischemic injury and apoptosis, but whether pharmacologic AMPK stimulation mitigates ischemia-reperfusion damage is unknown. The aims of this study were to determine whether direct stimulation of AMPK using a small molecule activator, A-769662, attenuates myocardial ischemia-reperfusion injury, and to examine its cardioprotective mechanisms. Isolated mouse hearts pre-treated with A-769662 had better recovery of left ventricular contractile function (55% vs. 29% of baseline rate-pressure product; p=0.03) and less myocardial necrosis (56% reduction in infarct size; p<0.01) during post-ischemic reperfusion compared to control hearts. Pre-treatment with A-769662 in vivo attenuated infarct size in C57Bl/6 mice undergoing left coronary artery occlusion and reperfusion compared to vehicle (36% vs. 18%, p=0.025). Mouse hearts with genetically inactivated AMPK were not protected by A-769662, indicating the specificity of this compound. Pre-treatment with A-769662 increased the phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2), preserved energy charge during ischemia, delayed the development of ischemic contracture, and reduced myocardial apoptosis and necrosis. A-769662 also augmented endothelial nitric oxide synthase (eNOS) activation during ischemia, which partially attenuated myocardial stunning, but did not prevent necrosis. AMPK is a therapeutic target that can be stimulated by a direct-acting small molecule in order to prevent injury during ischemia-reperfusion. The use of AMPK activators may represent a novel strategy to protect the heart and other solid organs against ischemia.
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Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
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Self-citationCharacterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding
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“Under selected conditions, the binding of A-769662 to the β subunit renders the phosphorylated Thr(172) residue resistant to protein phosphatases, thereby greatly promoting AMPK activation [23,24].”
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Cited by
AMP-activated protein kinase: new regulation, new roles?
Carling, D., Thornton, C., Woods, A., & Sanders, M. J. (2012) · Biochemical Journal · doi:10.1042/bj20120546 · Cited by 379
Srivastava, R. A. K., Pinkosky, S. L., Filippov, S., Hanselman, J. C., Cramer, C. T., & Newton, R. S. (2012) · Journal of Lipid Research · doi:10.1194/jlr.r025882 · Cited by 296
AMP-activated protein kinase regulation and biological actions in the heart
Zaha, V. G., & Young, L. H. (2012) · Circulation Research · doi:10.1161/circresaha.111.255505 · Cited by 279
Self-citationMitochondria as a Drug Target in Ischemic Heart Disease and Cardiomyopathy
Walters, A. M., Porter, G. A., & Brookes, P. S. (2012) · Circulation Research · doi:10.1161/circresaha.112.265660 · Cited by 271
Cao, Y., Bojjireddy, N., Kim, M., Li, T., Zhai, P., Nagarajan, N., Sadoshima, J., Palmiter, R. D., & Tian, R. (2017) · Circulation Research · doi:10.1161/circresaha.117.311159 · Cited by 74
Metadata
- Authors
- Kim, A. S., Miller, E. J., Wright, T. M., Li, J., Qi, D., Atsina, K., Zaha, V., Sakamoto, K., & Young, L. H.
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 51
- Issue
- 1
- Pages
- 24-32
- ISSN
- 0022-2828 (ISSN-L)
- OpenAlex
- W2137987407
- Cited by
- 171
- References
- 11
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
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