Hypoxia induces severe right ventricular dilatation and infarction in hemeoxygenase-1 null mice

Heme oxygenase (HO) catalyzes the oxidation of heme to generate carbon mono xide (CO) and bilirubin. CO increases cellular levels of cGMP, which regula tes vascular tone and smooth muscle development. Bilirubin is a potent anti oxidant. Hypoxia increases expression of the inducible HO isoform (HO-1) bu t not the constitutive isoform (HO-2). To determine whether HO-1 affects ce llular adaptation to chronic hypoxia in vivo, we generated HO-1 null (HO-1( -/-)) mice and subjected them to hypoxia (10% oxygen) for five to seven wee ks. Hypoxia caused similar increases in right ventricular systolic pressure in wild-type and HO-1(-/-) mice. Although ventricular weight increased in wild-type mice, the increase was greater in HO-1(-/-) mice. Similarly, the right ventricles were more dilated in HO-1(-/-) mice. After seven weeks of hypoxia, only HO-1(-/-) mice developed right ventricular infarcts with orga nized mural thrombi. No left ventricular infarcts were observed. Lipid pero xidation and oxidative damage occurred in right ventricular cardiomyocytes in HO-1(-/-), but not wild-type, mice. We also detected apoptotic cardiomyo cytes surrounding areas of infarcted myocardium by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assays. Our data sugge st that in the absence of HO-1, cardiomyocytes have a maladaptive response to hypoxia and subsequent pulmonary hypertension.