A novel pleiotropic effect of statins: prevention of cardiac hypertrophy by cholesterol-independent mechanisms.
Cardiac hypertrophy is an initial physiological adaptive response by the heart to pressure overload. However, if pressure overload persists, frequently, the heart decompensates and develops 'pathophysiological' hypertrophy. This leads to increased mortality and morbidity and is an independent risk factor for heart failure. Because cardiac myocytes convert this pressure overload into intracellular biochemical signals, blocking this critical signaling pathway may be an important therapeutic target to prevent cardiac hypertrophy. Small GTP-binding proteins, in particular Rac1, have been suggested to play a key role in the development of cardiac hypertrophy. Recently, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also called statins, have been shown to inhibit cardiac hypertrophy independent of their cholesterol lowering property. Statins block the isoprenylation and activation of members of the Rho family, such as RhoA and Rac1. Rac1 also regulates NADPH oxidase, which is a major source of reactive oxygen species (ROS) in cardiovascular cells. Growing evidence suggests that ROS may be involved in the process of cardiac hypertrophy and recent research has shown that statins attenuate oxidative stress through inhibition of Rac1. Overall, these pleiotropic effects of statins will give new insights into the process of cardiac hypertrophy.
Nakagami
Hironori
H
Vascular Medicine Research Unit, Brigham & Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Jensen
Kristin S
KS
Liao
James K
JK
D000975:Antioxidants / Q000494:pharmacology*; D006332:Cardiomegaly / Q000378:metabolism* / Q000517:prevention & control*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D017368:Protein Prenylation; D019821:Simvastatin / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013481:Superoxides; D019821:Simvastatin; D019255:NADPH Oxidases; D019204:GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein