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 Ca2+ properties were evaluated using an Ionoptix 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 Ca2+ fura-2 fluorescent intensity, and intracellular Ca2+ 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 Ca2+ levels without affecting time-to-90% relengthening and intracellular Ca2+ 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.
Aberle
Nicholas S
NS
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA.
Picklo
Matthew J
MJ
Amarnath
Venkataraman
V
Ren
Jun
J
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D003484:Cyanamide / Q000494:pharmacology; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000447:Aldehydes; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007093:Imidazoles; D011725:Pyridines; C462359:tert-4-hydroxy-2-nonenal; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D016257:Fura-2