doi: 10.1161/01.CIR.0000153800.09920.40
(Circulation. 2005;111:420-427.)
© 2005 American Heart Association, Inc.
Heart Failure |
Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload
From the Cardiovascular Medicine Section (E.K., W.S.C., F.S.), Boston University Medical Center, and the Myocardial Biology Unit (G.M.K., M.K.R., D.A.S., W.S.C., F.S.), Whitaker Cardiovascular Institute (R.L.), Boston University School of Medicine, Boston, Mass.
Correspondence to Flora Sam, MD, Myocardial Biology Unit, Department of Medicine, Boston University School of Medicine, 650 Albany St, Room X706, Boston, MA 02118. E-mail flora.sam{at}bmc.org
Received July 21, 2004; revision received September 20, 2004; accepted October 25, 2004.
Background— Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload.
Methods and Results— We used the mineralocorticoid receptor–selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4±0.1 versus 3.7±0.1 mm) and end-systolic (2.0±0.1 versus 2.5±0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42±2% versus 34±4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages.
Conclusions— Mineralocorticoid receptors play an important role in mediating the transition from LV hypertrophy to failure with chronic pressure overload. The effects of mineralocorticoid receptor stimulation are associated with alterations in the interstitial matrix and myocyte apoptosis and may be mediated, at least in part, by oxidative stress and inflammation.
Key Words: aldosterone • stress, oxidative • inflammation
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