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  • Although HK localizes mainly to either the cytosol

    2022-09-08

    Although HK localizes mainly to either the cytosol or mitochondria [29], [30], [31] and cardioprotection is associated with increased mitochondrial HK binding, some studies have identified a component of HK located in intracellular vesicles within the cardiomyocyte [48], [61], supporting older data that HK may also be associated with membrane structures other than mitochondria [62]. Although no changes in HK activity seems to occur in this microsomal compartment with ischemia or IPC, HK protein levels in this compartment during ischemia are affected by IPC [48]. It is conceivable that the HK in these microsomes is somehow involved in IPC, but further research will be necessary to elucidate the role, if any.
    Molecular actions of HK that impact mPTP opening during I/R
    HK and metabolic profiles in cancer, developing hearts, and normal and diseased adult hearts Differences in susceptibility to I/R injury and efficacy of IPC in various cells types in relation to their metabolic profiles may provide additional clues about the role of HK in cardioprotection. Specifically, cancer cells exhibit Warburg-like metabolic profiles characterized by enhanced carboxypeptidase glycolysis, reduced glucose oxidation, upregulated glycolytic enzymes (including HK) and down-regulated oxidative phosphorylation enzymes, elements of which are shared by neonatal hearts, and hypertrophied or failing adult hearts (Table 1). Neonatal hearts, like cancer cells, are intrinsically less susceptible to I/R injury, and are not further protected by IPC like normal adult hearts [94]. Hypertrophied and failing adult hearts, on the other hand, show some elements of the Warburg metabolic profile, but are not necessarily less susceptible to I/R injury or as effectively cardioprotected by IPC compared to normal adult hearts [95], [96], [97], [98]. Here we review the relationship between susceptibility to I/R injury, efficacy of IPC and the metabolic profiles in these different cell types.
    Summary, conclusions and therapeutic implications Based on the scope of direct anti-cell death and favorable metabolic actions of HKs during I/R, it is intriguing to speculate that enhanced HK binding to VDAC may be one of the long sought after end-targets of cardioprotective signaling. If so, then strategies to strengthen the HK–VDAC interaction may have therapeutic promise. Overexpression of HK2 has been shown to protect cultured neonatal myocytes from oxidative injury [53], but similar experiments have yet to be carried out in adult hearts. HK1 overexpression may be particularly promising, since HK1 remains bound to mitochondria and does not normally translocate to the cytoplasm like HK2. HK1 is also the predominant isoform in neonatal hearts, which are highly resistant to I/R injury, probably because they are already maximally cardioprotected. Cancer cells predominantly upregulate HK2 in massive amounts which confers cytoprotective effects. In hypertrophied adult hearts, however, the more modest upregulation of HK2 in concert with other glycolytic enzymes does not appear to confer increased resistance to I/R injury as in cancer cells. The difference may be that in cancer cells, basal Akt activity is typically high, thereby reinforcing HK2 binding to mitochondria. This is consistent with the finding that hypertrophied hearts can still be cardioprotected by IPC, suggesting that HK2 binding to mitochondria is not maximized. It should now be possible to explore these issues and the therapeutic potential of HK-based gene delivery techniques in adult hearts, by comparing the ability of HK1 and HK2, and corresponding HK mutants which lack either enzymatic activity or the mitochondrial binding motif, to protect against I/R injury.
    Funding sources This work was supported by the NIH/NHLBI grants R01 HL117385, HL101228, the American Heart Association Western States Affiliate Post-doctoral Research Fellowship11POST6110007, the American Heart Association Western States Affiliate Grant-in-Aid13GRNT14650074 and the Laubisch and Kawata endowments.