Targeting hexokinase II and its cellular distribution may provide a novel therapeutic option in ischemic heart disease

Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions; however, it is unknown how perturbations in glycolytic enzymes affect cardiac response to ischemia/reperfusion (I/R). Hexokinase (HK) II is a HK isoform that is expressed in the heart and can bind to the mitochondrial outer membrane.

In a study published in the January 2011 issue of Circulation Research, an international team of researchers involving Academy Professor Markku Laakso and Researcher Sami Heikkinen of the University of Eastern Finland sought to define how HKII and its binding to mitochondria play a role in cardiac response and remodelling after I/R. Sami Heikkinen and Markku Laakso originally generated heterozygous HKII knock-out (HKII+/–) mice at the University of Eastern Finland, Kuopio.

The researchers first showed that HKII levels and its binding to mitochondria are reduced 2 days after I/R and then subjected the hearts of wild-type and heterozygote HKII knockout (HKII+/–) mice to I/R by coronary ligation. At baseline, HKII+/– mice have normal cardiac function; however, they display lower systolic function after I/R compared to wild-type animals. The mechanism appears to be through an increase in cardiomyocyte death and fibrosis and a reduction in angiogenesis; the latter is through a decrease in hypoxia-inducible factor–dependent pathway signalling in cardiomyocytes. HKII mitochondrial binding is also critical for cardiomyocyte survival, because its displacement in tissue culture with a synthetic peptide increases cell death. Our results also suggest that HKII may be important for the remodelling of the viable cardiac tissue because its modulation in vitro alters cellular energy levels, O2 consumption, and contractility.

The results indicate that the HKII+/– mice are more susceptible to ischemic injury to their heart. This is attributable to an increase in cell death and fibrosis, a decrease in angiogenesis, and possibly a reduction in the contractility of the viable cardiomyocytes because of reduced energy production. Furthermore, the binding of HKII to mitochondria plays an important role in cardiomyocyte survival and protection against cell death. The results provide the first description of the role of HKII and its mitochondrial binding in acute cardiac I/R injury and subsequent remodelling of the intact heart. Thus, in addition to their role in cancer, HKII and its mitochondrial binding play a prominent role in the pathogenesis of ischemic heart disease. These data suggest that targeting HKII and its cellular distribution may provide a novel therapeutic option in ischemic heart disease.

                                                                                     

For further information, please contact Academy Professor Markku Laakso, markku.laakso@kuh.fi or Researcher Sami Heikkinen, sami.heikkinen@uef.fi

Original article:
Rongxue Wu ; Kirsten M. Smeele ; Eugene Wyatt ; Yoshihiko Ichikawa ; Otto Eerbeek ; Lin Sun ; Kusum Chawla ; Markus W. Hollmann ; Varun Nagpal ; Sami Heikkinen ; Markku Laakso ; Kentaro Jujo ; J. Andrew Wasserstrom ; Coert J. Zuurbier ; and Hossein Ardehali. Reduction in Hexokinase II Levels Results in Decreased Cardiac Function and Altered Remodeling After Ischemia/Reperfusion Injury. Circulation Research. 2011;108:60-69.

 

Artikkelin kirjoitusvuosi: 2011

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