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Effect of Targeting Mitogen-Activated Protein Kinase on Cardiac Remodeling in Rats

Department of Clinical Pharmacology, Alexandria University, Alexandria, Egypt, mnhbaraka{at}yahoo.com

Maher Mikhail, MD, PhD

Department of Clinical Pharmacology, Alexandria University, Alexandria, Egypt

Aida Guemei, MD, PhD

Department of Clinical Pharmacology, Alexandria University, Alexandria, Egypt

Samar El Ghotny, MD, PhD

Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Background: Increasing evidence suggests that the activation of p38 mitogen-activated protein kinase (p38MAPK) plays a role in cardiac remodeling. Targeting p38MAPK using drugs reported to interfere with its phosphorylation, namely statins and all-trans retinoic acid (atRA), might play a role in ameliorating this remodeling. Methods and Results: Cardiac remodeling was induced in male albino rats by chronic inhibition of nitric oxide (NO) synthesis by N-nitro L-arginine methyl ester (L-NAME). Daily oral administration of L-NAME for 4 weeks resulted in the elevation of mean arterial blood pressure (MABP) together with cardiac remodeling evidenced by an increase in left ventricular-body weight ratio together with an increase in cardiac hydroxyproline concentration and a decrease in left ventricular papillary muscle-developed tension. An elevation in cardiac phosphorylated p38MAPK concentration, tumor necrosis factor alpha concentration and in cardiac caspase 3 activity was also observed. Administration of either rosuvastatin or all-trans retinoic acid (atRA), starting 4 weeks after L-NAME administration, ameliorated remodeling and improved all studied parameters. Conclusions: Targeting MAPK might represent a useful therapeutic avenue to ameliorate cardiac remodeling and support the notion that atRA and statins are potential candidates for the prevention and therapy of cardiac remodeling.

Key Words: hypertrophy • MAPK • remodeling • retinoic acid • statins • rosuvastatin

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 4, 339-346 (2009)
DOI: 10.1177/1074248409349620


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