Inhibition of heme oxygenase?1 impairs cardiac muscle sensitivity to beta?adrenergic stimulation

Abstract

Heme oxygenase-1 (HO-1) is the inducible isoform of heme oxygenase and plays a role in defense against cellular stress. The effects of HO-1 on cardiac muscle contractility, however, are unknown. HO-1 was induced by intraperitoneal injection of hemin in rabbits 24 and 48 h before isolating right ventricular papillary muscles for mechanical in vitro analysis at baseline and during stimulation with isoprenalin. Western blotting and activity measurement con.rmed upregulation of HO-1 in ventricular tissue, and immunohistochemical stainings showed localization in the cardiac endothelium. Baseline mechanical performance of papillary muscles and maximal inotropic response to ISO was not significantly affected by HO-1 induction. Also, the log(EC50) of the ISO concentration-response curve was not affected by HO-1 induction. Inhibition of heme oxygenase with stanneous mesoporphyrin or chromium mesoporphyrin in muscles with induced HO-1, however, shifted the log(EC50) of the ISO concentration-response curve from -6.9 +/- 0.2 to -6.0 +/- 0.2 (p = 0.008). These results indicate that induction of cardiac HO-1 has no direct effect on baseline contractility. Pharmacological inhibition of HO-1 upon induction, however, diminishes cardiac muscle sensitivity to beta-adrenergic stimulation. These results caution against pharmacologically targeting HO-1 when an activated adrenergic system is important for hemodynamic stability.