Heme oxygenase‐1 (HO‐1) inhibits pro‐oxidant induced hypertrophy of HL‐1 cardiomyocytes

Reactive oxygen species (ROS) activate multiple signaling pathways involved in cardiac hypertrophy. We showed that hemin reduces hypertrophy in response to pressure overload, in association with increased HO‐1 and decreased ROS. Since HO‐1 exerts potent anti‐oxidant effects, we hypothesized that this enzyme inhibits ROS‐induced cardiomyocyte hypertrophy. HL‐1 cardiomyocytes were transduced with adenovirus expressing HO‐1 (AdHO‐1) or treated with 25μM hemin for 24 hrs to increase basal HO‐1 expression, and then exposed to 200 μM H 2 O 2 . Hypertrophy was measured using planar morphometry and 3 H‐leucine incorporation 48 hr after H 2 O 2 exposure. H 2 O 2 induced myocyte hypertrophy in a dose‐dependent manner. The hypertrophic effect of H 2 O 2 was partially reversed by N‐acetyl cysteine. Hemin decreased ROS generation and reduced H 2 O 2 ‐induced increases in cell size and leucine incorporation. The effect of hemin was mimicked by AdHO‐1 and bilirubin, and was inhibited by HO‐1 siRNA. HO‐1 overexpression significantly reduced pro‐oxidant‐induced increase in promoter and DNA binding activities of NF‐κB, and inhibition of NF‐κB nuclear translocation with SN50 inhibited pro‐oxidant induced cardiomyocyte hypertrophy, suggesting that the anti‐hypertrophic effects HO‐1 may be mediated, at least in part, by inhibition of NF‐κB. These results demonstrate that HO‐1 inhibits pro‐oxidant induced cardiomyocyte hypertrophy and suggest that HO‐1 may yield therapeutic potential in treatment of cardiac hypertrophy and prevention of heart failure. Supported by grants from CIHR to LG Melo and CA Ward.