Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice
Shaw-Fang Yet, … , Stella Kourembanas, Mu-En Lee
Shaw-Fang Yet, … , Stella Kourembanas, Mu-En Lee
Published April 15, 1999
Citation Information: J Clin Invest. 1999;103(8):R23-R29. https://doi.org/10.1172/JCI6163.
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Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice

Abstract

Heme oxygenase (HO) catalyzes the oxidation of heme to generate carbon monoxide (CO) and bilirubin. CO increases cellular levels of cGMP, which regulates vascular tone and smooth muscle development. Bilirubin is a potent antioxidant. Hypoxia increases expression of the inducible HO isoform (HO-1) but not the constitutive isoform (HO-2). To determine whether HO-1 affects cellular 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 weeks. 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 organized mural thrombi. No left ventricular infarcts were observed. Lipid peroxidation and oxidative damage occurred in right ventricular cardiomyocytes in HO-1–/–, but not wild-type, mice. We also detected apoptotic cardiomyocytes surrounding areas of infarcted myocardium by terminal deoxynucleotide transferase–mediated dUTP nick end-labeling (TUNEL) assays. Our data suggest that in the absence of HO-1, cardiomyocytes have a maladaptive response to hypoxia and subsequent pulmonary hypertension.

Authors

Shaw-Fang Yet, Mark A. Perrella, Matthew D. Layne, Chung-Ming Hsieh, Koji Maemura, Lester Kobzik, Philippe Wiesel, Helen Christou, Stella Kourembanas, Mu-En Lee

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Chronic hypoxia increases right ventricular systolic pressure and ventri...
Chronic hypoxia increases right ventricular systolic pressure and ventricular weight in wild-type and HO-1–/– mice. Wild-type (+/+) and HO-1 null (–/–) mice were exposed to normoxia or chronic hypoxia (10% oxygen). (a) Right ventricular systolic pressure was measured under normoxic conditions (open bars) or after five weeks of hypoxia (filled bars). Error bars indicate standard deviations. *P < 0.05 vs. animals exposed to normoxia within the same group (n = 5 in each group). (b) Ventricular weight in wild-type and HO-1–/– mice was measured under normoxic conditions (n = 6 in each group) or after seven weeks of hypoxia (n = 5 in each group) and expressed as a ratio of ventricular weight (milligrams) to total body weight (grams). The value obtained for normoxic wild-type mice (4.46 ± 0.52) was set as 100%. The ventricular weight index for mice housed under normoxic (open bars) or hypoxic (filled bars) conditions is expressed relative to the value for normoxic wild-type mice. Error bars indicate standard deviations. *P < 0.05 vs. animals exposed to normoxia within the same group. #P < 0.05 vs. wild-type animals exposed to hypoxia.