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
This article has been cited by other articles:
 |
|
 |
|
  D. S. De Silva, R. M. Wilson, C. Hutchinson, P. C. Ip, A. G. Garcia, S. Lancel, M. Ito, D. R. Pimentel, and F. Sam Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1983 - H1993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jeong, D. F. Chaupin, K. Matsushita, M. Yamakuchi, S. J. Cameron, C. N. Morrell, and C. J. Lowenstein Aldosterone activates endothelial exocytosis PNAS, March 10, 2009; 106(10): 3782 - 3787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Qu, F. M. Volpicelli, L. I. Garcia, N. Sandeep, J. Zhang, L. Marquez-Rosado, P. D. Lampe, and G. I. Fishman Gap Junction Remodeling and Spironolactone-Dependent Reverse Remodeling in the Hypertrophied Heart Circ. Res., February 13, 2009; 104(3): 365 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Oyamada, M. Sone, K. Miyashita, K. Park, D. Taura, M. Inuzuka, T. Sonoyama, H. Tsujimoto, Y. Fukunaga, N. Tamura, et al. The Role of Mineralocorticoid Receptor Expression in Brain Remodeling after Cerebral Ischemia Endocrinology, August 1, 2008; 149(8): 3764 - 3777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Zick, B. Gillespie, and K. D. Aaronson The effect of Crataegus oxycantha special extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure Eur J Heart Fail, June 1, 2008; 10(6): 587 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Iwazu, S. Muto, G. Fujisawa, E. Nakazawa, K. Okada, S. Ishibashi, and E. Kusano Spironolactone Suppresses Peritubular Capillary Loss and Prevents Deoxycorticosterone Acetate/Salt-Induced Tubulointerstitial Fibrosis Hypertension, March 1, 2008; 51(3): 749 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Terada, H. Kuwana, T. Kobayashi, T. Okado, N. Suzuki, T. Yoshimoto, Y. Hirata, and S. Sasaki Aldosterone-Stimulated SGK1 Activity Mediates Profibrotic Signaling in the Mesangium J. Am. Soc. Nephrol., February 1, 2008; 19(2): 298 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. LeBrasseur, T.-A. S. Duhaney, D. S. De Silva, L. Cui, P. C. Ip, L. Joseph, and F. Sam Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension Hypertension, September 1, 2007; 50(3): 489 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Stas, A. Whaley-Connell, J. Habibi, L. Appesh, M. R. Hayden, P. R. Karuparthi, M. Qazi, E. M. Morris, S. A. Cooper, C. D. Link, et al. Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin-Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling Endocrinology, August 1, 2007; 148(8): 3773 - 3780. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-A. S. Duhaney, L. Cui, M. K. Rude, N. K. Lebrasseur, S. Ngoy, D. S. De Silva, D. A. Siwik, R. Liao, and F. Sam Peroxisome Proliferator-Activated Receptor {alpha}-Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload Hypertension, May 1, 2007; 49(5): 1084 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Bergman, J. R. Teerlink, R. Mahimkar, L. Li, B.-Q. Zhu, A. Nguyen, S. Dahi, J. S. Karliner, and D. H. Lovett Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1847 - H1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Cascella, S. Palomba, L. Tauchmanova, F. Manguso, S. Di Biase, D. Labella, F. Giallauria, C. Vigorito, A. Colao, G. Lombardi, et al. Serum Aldosterone Concentration and Cardiovascular Risk in Women with Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4395 - 4400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hilfiker-Kleiner, U. Landmesser, and H. Drexler Molecular Mechanisms in Heart Failure: Focus on Cardiac Hypertrophy, Inflammation, Angiogenesis, and Apoptosis J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A56 - A66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Satoh, Y Ishikawa, Y Minami, T Akatsu, and M Nakamura Eplerenone inhibits tumour necrosis factor alpha shedding process by tumour necrosis factor alpha converting enzyme in monocytes from patients with congestive heart failure. Heart, July 1, 2006; 92(7): 979 - 980. [Full Text] [PDF]
|
|
|
|
|
|
N. Kobayashi, K. Yoshida, S. Nakano, T. Ohno, T. Honda, Y. Tsubokou, and H. Matsuoka Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts Hypertension, April 1, 2006; 47(4): 671 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nagata, K. Obata, J. Xu, S. Ichihara, A. Noda, H. Kimata, T. Kato, H. Izawa, T. Murohara, and M. Yokota Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats Hypertension, April 1, 2006; 47(4): 656 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Deschamps and F. G. Spinale Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation Cardiovasc Res, February 15, 2006; 69(3): 666 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takai, D. Jin, M. Muramatsu, K. Kirimura, H. Sakonjo, and M. Miyazaki Eplerenone Inhibits Atherosclerosis in Nonhuman Primates Hypertension, November 1, 2005; 46(5): 1135 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Rude, T.-A. S. Duhaney, G. M. Kuster, S. Judge, J. Heo, W. S. Colucci, D. A. Siwik, and F. Sam Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular Cardiomyocytes Hypertension, September 1, 2005; 46(3): 555 - 561. [Abstract] [Full Text] [PDF]
|
|