Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion.

Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by 18F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury.

Nerve growth factor rescues diabetic mice heart after ischemia/reperfusion injury via up-regulation of the TRPV1 receptor.

AIMS: Nerve growth factor (NGF), a member of the neurotrophin family, plays an essential role in diabetic neuropathy and ischemic heart disease. In the present study, we explored the potential role of NGF and the involvement of TRPV1 receptor in isolated diabetic mouse hearts following ischemia/reperfusion (I/R) injury. METHODS: Adenovirus-mediated NGF gene delivery was performed on diabetic and sham hearts 8weeks after streptozotocin treatment. The sciatic nerve conduction velocity was recorded using a biological signal acquisition system. Forty-eight hours after heart surgery, mice were subjected to I/R injury using a Langendorff system. Several cardiac parameters and the expression of associated molecules were analyzed during the experiment. RESULTS: The sciatic nerve conduction velocity was reduced in diabetic mice compared with that in control mice. Decreased expression of NGF, TRPV1, and the downstream neurotransmitters CGRP and SP was observed in the diabetic hearts. Adenovirus-mediated NGF overexpression reversed the reduction in TRPV1 and downstream neuropeptides, resulting in improved cardiac recovery post-I/R injury in diabetic hearts. The protective effect of NGF was abolished by CGRP8-37 (a selective CGRP antagonist), while it was preserved by low-dose capsaicin. CONCLUSIONS: The NGF-induced up-regulation of TRPV1 via the increased synthesis and release of endogenous CGRP leads to improved cardiac performance in I/R-injured diabetic heart.

Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.

Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.

Early contrast-enhanced MRI predicts late functional recovery after reperfused myocardial infarction.

BACKGROUND: We have observed 3 abnormal patterns on contrast-enhanced MRI early after reperfused myocardial infarction (MI): (1) absence of normal first-pass signal enhancement (HYPO), (2) normal first pass signal followed by hyperenhanced signal on delayed images (HYPER), or (3) both absence of normal first-pass enhancement and delayed hyperenhancement (COMB). This study examines the association between these patterns in the first week after MI and late recovery of myocardial contractile function by use of magnetic resonance myocardial tissue tagging. METHODS AND RESULTS: Seventeen patients (14 men) with a mean age of 53+/-12 years were studied after a reperfused first MI. Contrast-enhanced images were acquired immediately after bolus administration of gadolinium and 7+/-2 minutes later. Tagged images were acquired at weeks 1 and 7. Circumferential segment shortening (%S) was measured in regions displaying HYPER, COMB, or HYPO contrast patterns and in remote regions (REMOTE) at weeks 1 and 7. At week 1, %S was depressed in HYPER, COMB, and HYPO (9+/-8%, 7+/-6%, and 5+/-4%, respectively) and were less than REMOTE (18+/-6%, P<0.003). However, in HYPER, %S improved at week 7 from 9+/-8% to 18+/-5% (P<0.001 versus week 1). In contrast, HYPO did not improve significantly (5+/-4% to 6+/-3%, P=NS) and COMB tended to improve 7+/-6% to 11+/-6% (P=0.06). CONCLUSIONS: HYPER has partially reversible dysfunction and represents predominantly viable myocardium. COMB shows borderline improvement and likely contains an admixture of viable and necrotic myocardium. HYPO shows little functional improvement at 7 weeks, presumably because of irreversible myocardial damage.