Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension.
Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (n=14) or treated with fenofibrate 100 mg/kg per day (n=12) for 1 week before and 4 weeks after surgery. Aldosterone increased systolic blood pressure in untreated mice versus saline-untreated mice (134+/-3 versus 91+/-3 mm Hg; P<0.01). This was unaffected by fenofibrate (131+/-3 mm Hg). Aldosterone increased LV end-diastolic and end-systolic dimensions, which were significantly attenuated by fenofibrate (3.8+/-0.1 versus 3.5+/-0.1 mm, and 1.5+/-0.1 versus 1.15+/-0.1 mm, respectively). Fenofibrate also decreased aldosterone-induced LV hypertrophy (LV weight/body weight, 4.1+/-0.2 versus 4.6+/-0.1 mg/g) and improved percent LV fractional shortening (67+/-7% versus 60+/-2%). Additionally, fenofibrate ameliorated the increased matrix metalloproteinase-2/tissue inhibitors of metalloproteinase-2 ratio and fibrosis seen in aldosterone-untreated hearts (P<0.05 for both). Furthermore, in aldosterone-untreated hearts, fenofibrate decreased transforming growth factor-beta, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-alpha, peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression, and acetyl coenzyme A carboxylase phosphorylation (P<0.05 for all) in aldosterone-infused hearts; uncoupling protein-3 and medium-chain acyl coenzyme A dehydrogenase protein expression decreased with fenofibrate (P<0.05 and P<0.01, respectively, versus aldosterone-infused), suggesting that improved myocardial remodeling is independent of fatty acid oxidation. Thus, fenofibrate improved aldosterone-induced LV hypertrophy independently of an effect on blood pressure with decreased fibrosis and altered extracellular matrix.
Lebrasseur
Nathan K
NK
Muscle and Aging Research Unit, Boston University School of Medicine, MA 02118, USA.
Duhaney
Toni-Ann S
TA
De Silva
Deepa S
DS
Cui
Lei
L
Ip
Peter C
PC
Joseph
Lija
L
Sam
Flora
F
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D013599:Systole; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
D047492:Peroxisome Proliferator-Activated Receptors; D019716:Tissue Inhibitor of Metalloproteinase-2; D000450:Aldosterone; D020778:Matrix Metalloproteinase 2; D011345:Fenofibrate