Lovastatin inhibits phenylephrine-induced ERK activation and growth of cardiac.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) exert numerous cellular effects through the inhibition of cholesterol synthesis. The objectives of these experiments were to determine the following: (1) whether lovastatin (LOV) inhibits phenylephrine (PE)-induced growth of neonatal rat cardiac myocytes without inducing cytotoxicity and (2) whether growth-inhibiting effects of LOV are associated with reduced PE activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). After 48 h of exposure, LOV alone (0.1-10 microM) inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) reduction without significant changes in propidium iodide staining, and 100 microM mevalonic acid prevented the effect of LOV on MTT reduction. PE (50 or 100-microM for 48 h) induced significant increases in protein-to-DNA ratios. PE (100 microM for 5 min) significantly increased the phosphorylated forms of ERK 1 and ERK 2 and activity of ERK. After 24 h pretreatment or 48 h cotreatment, LOV (10 microM) significantly inhibited PE-induced growth. In addition, LOV pretreatment significantly inhibited the stimulatory effect of PE on ERK 2 phosphorylation and ERK activity. These results demonstrate that LOV, at concentrations that do not alter membrane integrity, inhibits PE-induced growth of cardiac myocytes, potentially through reduced activation of ERK 1/2.
Melchert
R B
RB
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, AR 72205, USA. MelchertRussellB@uams.edu
Liu
H
H
Granberry
M C
MC
Kennedy
R H
RH
D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000633:toxicity; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000517:prevention & control; D002478:Cells, Cultured; D004396:Coloring Agents; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D008148:Lovastatin / Q000494:pharmacology* / Q000633:toxicity; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D010656:Phenylephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010766:Phosphorylation; D017035:Pravastatin / Q000633:toxicity; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013844:Thiazoles
D000924:Anticholesteremic Agents; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D010656:Phenylephrine; D011419:Propidium; D008148:Lovastatin; D020928:Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; D017035:Pravastatin