Myeloperoxidase impairs the contractile function in isolated human cardiomyocytes.

Abstract We set out to characterize the mechanical effects of myeloperoxidase (MPO) in isolated left-ventricular human cardiomyocytes. Oxidative myofilament protein modifications (sulfhydryl (SH)-group oxidation and carbonylation) induced by the peroxidase and chlorinating activities of MPO were additionally identified. The specificity of the MPO-evoked functional alterations was tested with an MPO inhibitor (MPO-I) and the antioxidant amino acid Met. The combined application of MPO and its substrate, hydrogen peroxide (H 2 O 2 ), largely reduced the active force ( F active ), increased the passive force ( F passive ), and decreased the Ca 2+ sensitivity of force production ( p Ca 50 ) in permeabilized cardiomyocytes. H 2 O 2 alone had significantly smaller effects on F active and F passive and did not alter p Ca 50 . The MPO-I blocked both the peroxidase and the chlorinating activities, whereas Met selectively inhibited the chlorinating activity of MPO. All of the MPO-induced functional effects could be prevented by the MPO-I and Met. Both H 2 O 2 alone and MPO + H 2 O 2 reduced the SH content of actin and increased the carbonylation of actin and myosin-binding protein C to the same extent. Neither the SH oxidation nor the carbonylation of the giant sarcomeric protein titin was affected by these treatments. MPO activation induces a cardiomyocyte dysfunction by affecting Ca 2+ -regulated active and Ca 2+ -independent passive force production and myofilament Ca 2+ sensitivity, independent of protein SH oxidation and carbonylation. The MPO-induced deleterious functional alterations can be prevented by the MPO-I and Met. Inhibition of MPO may be a promising therapeutic target to limit myocardial contractile dysfunction during inflammation.