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 oxygenase (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.
Liu
Xiaoli
X
Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis St., Thorn 932A, Boston, MA 02115, USA.
Wei
Jiao
J
Peng
David H
DH
Layne
Matthew D
MD
Yet
Shaw-Fang
SF
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress
D008565:Membrane Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse