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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #147697
Title: MALONDIALDEHYDE INHIBITS CARDIAC CONTRACTILE FUNCTION IN VENTRICULAR MYOCYTES VIA A P38 MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT MECHANISM

Author
item FOLDEN, DAVID - UNIV OF NORTH DAKOTA
item GUPTA, AKANKSHA - ND STATE UNIVERSITY
item SHARMA, AVADHESH - ND STATE UNIVERSITY
item LI, SHIYAN - UNIV OF NORTH DAKOTA
item Saari, Jack
item REN, JUN - UNIV OF NORTH DAKOTA

Submitted to: British Journal of Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/2003
Publication Date: 6/23/2003
Citation: Folden, D.V., Gupta, A., Sharma, A.C., Li, S-Y., Saari, J.T., Ren, J. Malondialdehyde inhibits cardiac contractile function in ventricular myocytes via a p38 mitogen-activated protein kinase-dependent mechanism. British Journal of Pharmacology. 2003. v.139. p.1310-1316.

Interpretive Summary: Oxygen-derived free radicals are chemical by-products of normal metabolic reactions and are highly reactive and potentially damaging to tissues. Exaggerated production of or reduced protection against these free radicals have been implicated as a cause of heart disease. When these reactive oxygen species react with lipids in the body, one of the products is malondialdehyde (MDA), a chemical that we hypothesized may be a cause of impaired heart function. To test this hypothesis, isolated rat heart cells were placed under a microscope and electrically stimulated to contract in the presence or absence of MDA. MDA treatment impaired the rate at which cells contracted, their maximum ability to shorten and their ability to exchange calcium, a key mineral in causing heart cells to contract. The impairment of function by MDA was inhibited in the presence of vitamin C, an antioxidant, or by an agent that inhibits a specific molecular signaling pathway known to be activated by oxidative stress and implicated in heart disease. These findings indicate that MDA, produced by oxidative stress, may itself act as an oxidative stressor and that a signaling pathway already implicated in heart disease is activated by MDA. These findings will be useful to scientists and consumers interested in the pathology associated with heart disease.

Technical Abstract: Increased oxidative stress plays a significant role in the etiology of cardiovascular disease. Lipid peroxidation, initiated in the presence of hydroxyl radicals resulting in the production of malondialdehyde, directly produces oxidative stress. This study was designed to examine the direct impact of malondialdehyde on ventricular contractile function at the single cardiac myocyte level. Ventricular myocytes from adult rat hearts were stimulated to contract at 0.5 Hz, and mechanical and intracellular Ca2+ properties were evaluated using an IonOptix Myocam® system. Contractile properties analyzed included peak shortening amplitude (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt), and Ca2+ -induced intracellular Ca2+ fluorescence release (CICR) and intracellular Ca2+ decay (tau). P38 mitogen-activated protein (MAP) kinase phosphorylation was assessed with Western blot. Our results indicated that malondialdehyde directly depressed PS ± dL/dt and CICR in a concentration-dependent manner and shortened TPS without affecting TR90 and tau. Interestingly, the malondialdehyde-induced cardiac mechanical effect was abolished by both the p38 MAP kinase inhibitor SB203580 (1 and 10 microM) and the antioxidant vitamin C (100 microM). Western blot analysis confirmed direct phosphorylation of p38 MAP kinase by malondialdehyde. These findings revealed a novel role of malondialdehyde and p38 MAP kinase in lipid peroxidation and oxidative stress-associated cardiac dysfunction.