Rationale: Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria. It is unknown whether mitochondria-bound hexokinase is mandatory for ischemic preconditioning and normal functioning of the intact, beating heart. Objective: We hypothesized that reducing mitochondrial hexokinase would abrogate ischemic preconditioning and disrupt myocardial function. Methods and Results: Ex vivo perfused HKII؉/؊ hearts exhibited increased cell death after ischemia and reperfusion injury compared with wild-type hearts; however, ischemic preconditioning was unaffected. To investigate acute reductions in mitochondrial HKII levels, wild-type hearts were treated with a TAT control peptide or a TAT-HK peptide that contained the binding motif of HKII to mitochondria, thereby disrupting the mitochondrial HKII association. Mitochondrial hexokinase was determined by HKI and HKII immunogold labeling and electron microscopy analysis. Low-dose (200 nmol/L) TAT-HK treatment significantly decreased mitochondrial HKII levels without affecting baseline cardiac function but dramatically increased ischemiareperfusion injury and prevented the protective effects of ischemic preconditioning. Treatment for 15 minutes with high-dose (10 mol/L) TAT-HK resulted in acute mitochondrial depolarization, mitochondrial swelling, profound contractile impairment, and severe cardiac disintegration. The detrimental effects of TAT-HK treatment were mimicked by mitochondrial membrane depolarization after mild mitochondrial uncoupling that did not cause direct mitochondrial permeability transition opening. Conclusions:Acute low-dose dissociation of HKII from mitochondria in heart prevented ischemic preconditioning, whereas high-dose HKII dissociation caused cessation of cardiac contraction and tissue disruption, likely through an acute mitochondrial membrane depolarization mechanism. The results suggest that the association of HKII with mitochondria is essential for the protective effects of ischemic preconditioning and normal cardiac function through maintenance of mitochondrial potential. (Circ Res. 2011;108:1165-1169.)
Blood flow is distributed through the heart muscle via a system of vessels forming the coronary circulation. The perfusion of the myocardium can be hampered by atherosclerosis creating localized obstructions in the epicardial vessels or by microvascular disease. In early stages of the disease, these impediments to blood flow are offset by dilation of the resistance vessels, which normally compensates for a decrease in perfusion pressure or increased metabolism. However, this dilatory reserve can become exhausted, which in general occurs first at the deeper layers of the heart wall where intramural vessels are subjected to compressive forces related to heart contraction. In the catheterization laboratory, guide wires of 0.33 mm diameter are available that are equipped with a pressure and flow velocity sensor at the tip, which can be positioned distal to the stenosis. These signals provide information about the impediment of the stenosis on coronary flow and allow for the evaluation of the status of the microcirculation. However, the interpretation of these signals is strongly model-dependent and therefore it is of paramount importance to develop realistic models reflecting the anatomy and unique physiology of the coronary circulation.
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