Abstract-Heme oxygenase (HO)-1 degrades the pro-oxidant heme and generates carbon monoxide and antioxidant bilirubin. We have previously shown that in response to hypoxia, HO-1-null mice develop infarcts in the right ventricle of their hearts and that their cardiomyocytes are damaged by oxidative stress. To test whether HO-1 protects against oxidative injury in the heart, we generated cardiac-specific transgenic mice overexpressing different levels of HO-1. By use of a Langendorff preparation, hearts from transgenic mice showed improved recovery of contractile performance during reperfusion after ischemia in an HO-1 dose-dependent manner. In vivo, myocardial ischemia and reperfusion experiments showed that infarct size was only 14.7% of the area at risk in transgenic mice compared with 56.5% in wild-type mice. Hearts from these transgenic animals had reduced inflammatory cell infiltration and oxidative damage. Our data demonstrate that overexpression of HO-1 in the cardiomyocyte protects against ischemia and reperfusion injury, thus improving the recovery of cardiac function. Key Words: heart Ⅲ infarction Ⅲ Langendorff preparation Ⅲ cytoprotection Ⅲ inflammation O xidative stress in the heart caused by ischemia and reperfusion leads to cardiomyocyte death. 1-3 Several studies have shown that increased expression of myocardial stress proteins and/or antioxidant enzymes protects against postischemic injury. 4 -6 In response to stress, elevated expression of heat shock proteins may protect the myocardium. 7 These heat shock proteins are thought to mediate cardioprotection through their biological functions as molecular chaperones by preventing protein denaturation. 7 Heme oxygenase (HO)-1, a stress response and cytoprotective protein, also known as hsp32, protects cells from death due to pathophysiological stress. 8 -12 By degrading the pro-oxidant heme and generating the antioxidant bilirubin, 13,14 HO-1 may protect cells against oxidative injury. In addition, carbon monoxide (CO), another HO-1 reaction product, contributes to the regulation of vascular tone and is reported to have antiinflammatory properties, which may contribute to the cytoprotective action of HO-1. 15,16 HO-1 is upregulated in the heart and blood vessels in response to hemodynamic stress in rats 17,18 and ischemia/ reperfusion injury in pigs, 19,20 implicating an important role for HO-1 in cardiovascular homeostasis. We have recently shown that in response to hypoxia, HO-1-null mice develop right ventricular infarcts with organized mural thrombi. Furthermore, increased lipid peroxidation and oxidative damage occur in right ventricular cardiomyocytes from HO-1-null but not wild-type mice. 12 Thus, we hypothesized that HO-1 may play a central role in cardiac homeostasis by protecting cardiomyocytes from ischemia/reperfusioninduced injury and secondary oxidative damage. To gain insight into the cardioprotective role of HO-1 in vivo, we generated transgenic mice overexpressing HO-1 specifically in the heart. We measured cardiac performance during ...

To examine the role of heme oxygenase (HO)-1 in the pathophysiology of vascular diseases, we generated mice deficient in both HO-1 and apolipoprotein E (HO-1-/-apoE-/-). Despite similar total plasma cholesterol levels in response to hypercholesterolemia, HO-1-/-apoE-/- mice, in comparison with HO-1+/+apoE-/- mice, had an accelerated and more advanced atherosclerotic lesion formation. In addition to greater lipid accumulation, these advanced lesions from HO-1-/-apoE-/- mice contained macrophages and smooth muscle alpha-actin-positive cells. We further tested the role of HO-1 on neointimal formation in a mouse model of vein graft stenosis. Autologous vein grafts in HO-1-/- mice showed robust neointima consisting of alpha-actin-positive vascular smooth muscle cells (VSMC) 10 days after surgery in comparison to the smaller neointima formed in autologous vein grafts in HO-1+/+ mice. However, at 14 days after surgery, the neointima from composite vessels of HO-1-/- mice was composed mainly of acellular material, indicative of substantial VSMC death. VSMC isolated from HO-1-/- mice were susceptible to oxidant stress, leading to cell death. Our data demonstrate that HO-1 plays an essential protective role in the pathophysiology of atherosclerosis and vein graft stenosis.

These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.