TY - JOUR
T1 - Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension
AU - LeBrasseur, Nathan K.
AU - Duhaney, Toni Ann S.
AU - De Silva, Deepa S.
AU - Cui, Lei
AU - Ip, Peter C.
AU - Joseph, Lija
AU - Sam, Flora
PY - 2007/9
Y1 - 2007/9
N2 - 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-α 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-β, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ coactivator-1α 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.
AB - 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-α 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-β, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ coactivator-1α 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.
KW - Aldosterone
KW - Cardiac remodeling
KW - Fibrosis
KW - Hypertension
KW - Matrix metalloproteinases
KW - Peroxisome proliferatoractivated receptor-α
UR - http://www.scopus.com/inward/record.url?scp=34548186958&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548186958&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.107.092403
DO - 10.1161/HYPERTENSIONAHA.107.092403
M3 - Article
C2 - 17606858
AN - SCOPUS:34548186958
SN - 0194-911X
VL - 50
SP - 489
EP - 496
JO - Hypertension
JF - Hypertension
IS - 3
ER -