Absence of heme oxygenase-1 exacerbates myocardial ischemia/reperfusion injury in diabetic mice

Increased production of reactive oxygen species contributes to the etiology of diabetes complications. Pathophysiological stimuli that increase oxidative stress upregulate heme oxygenate (HO)-1, a cytoprotective heme-degrading enzyme. We hypothesized that HO-1 may be important in myocardial injury that is exacerbated by diabetes. To test this hypothesis, the left anterior descending coronary arteries of nondiabetic and diabetic wild-type (HO-1^+/+) and HO-1 null (HO-1^-/-) mice were ligated for 1 h followed by 24 h reperfusion. The absence of HO-1 significantly increased myocardial infarct size (36.4 ± 2.0 vs. 21.4 ± 1.8% in HO-1^+/+ mice), while cardiac-specific overexpression of HO-1 protected against myocardial ischemic injury in diabetic mice. Despite similar high blood glucose levels, diabetic HO-1^-/- mice had fourfold higher oxidative stress and larger infarcts (56.0 ± 2.8%) than diabetic HO-1^+/+ mice (30.8 ± 6.1%). Moreover, hyperglycemia increased the mortality of HO-1^-/- mice (31.3%) after ischemia/reperfusion injury, and 55% of diabetic HO-1 ^-/- mice had mural thrombi in the left ventricles. The increased mortality of diabetic HO-1^-/- mice may be in part due to formation of left ventricular mural thrombi. Our data demonstrate that the absence of HO-1 renders animals more susceptible to myocardial ischemia/reperfusion damage and diabetes worsens the injury.