Inhibition of Cardiac Myocyte Contraction by 4-Hydroxy-Trans-2-Nonenal

Lipid peroxidation, initiated by hydroxyl radicals, results in production of 4-Hydroxy-trans-2-nonenal (HNE) and leads to cardiac injury. However, impact of HNE on ventricular function has not been clearly defined. This study was to examine the direct effect of HNE on cardiac contractile function at cardiac myocyte level. Adult male rat ventricular myocytes were isolated and electrically stimulated to contract at 0.5 Hz. Mechanical and intracellular Ca 2+ properties were evaluated using an lonoptix Myocam® system. Contractile properties analyzed included peak shortening (PS), time-PS, time-to-90% relengthening, maximal velocities of shortening and relengthening (±dL/dt), change of electrically stimulated intracellular Ca 2+ fura-2 fluorescent intensity, and intracellular Ca 2+ decay. Our results indicated that short-term incubation of HNE (10 -6 to 10 -4 M) with myocytes depressed PS, ±dL/dt, and fura-2 fluorescent intensity; shortened time-PS; and elevated resting intracellular Ca 2+ levels without affecting time-to-90% relengthening and intracellular Ca 2+ decay. Interestingly, the HNE-induced cardiac mechanical effects (with the exception of shortened time-PS) were abolished by either the aldehyde dehydrogenase inhibitor cyanamide or the p38 mitogen-activated protein kinase inhibitor SB203580. These findings reveal a possible role of HNE in the lipid peroxidation-associated cardiac contractile dysfunction that is likely mediated through HNE metabolism and mitogen-activated protein kinase activation.