Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension

Nathan K LeBrasseur, Toni Ann S Duhaney, Deepa S. De Silva, Lei Cui, Peter C. Ip, Lija Joseph, Flora Sam

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)489-496
Number of pages8
JournalHypertension
Volume50
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

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Fenofibrate
Aldosterone
Hypertension
Left Ventricular Hypertrophy
Peroxisome Proliferator-Activated Receptors
Fibrosis
Blood Pressure
Phosphorylation
Diastolic Heart Failure
Acyl-CoA Dehydrogenase
Acetyl-CoA Carboxylase
Tissue Inhibitor of Metalloproteinase-2
Collagen Type III
Matrix Metalloproteinase 2
Extracellular Signal-Regulated MAP Kinases
Transforming Growth Factors
Collagen Type I
Matrix Metalloproteinases
Drinking Water
Muscle Cells

Keywords

  • Aldosterone
  • Cardiac remodeling
  • Fibrosis
  • Hypertension
  • Matrix metalloproteinases
  • Peroxisome proliferatoractivated receptor-α

ASJC Scopus subject areas

  • Internal Medicine

Cite this

LeBrasseur, N. K., Duhaney, T. A. S., De Silva, D. S., Cui, L., Ip, P. C., Joseph, L., & Sam, F. (2007). Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. Hypertension, 50(3), 489-496. https://doi.org/10.1161/HYPERTENSIONAHA.107.092403

Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. / LeBrasseur, Nathan K; Duhaney, Toni Ann S; De Silva, Deepa S.; Cui, Lei; Ip, Peter C.; Joseph, Lija; Sam, Flora.

In: Hypertension, Vol. 50, No. 3, 09.2007, p. 489-496.

Research output: Contribution to journalArticle

LeBrasseur, NK, Duhaney, TAS, De Silva, DS, Cui, L, Ip, PC, Joseph, L & Sam, F 2007, 'Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension', Hypertension, vol. 50, no. 3, pp. 489-496. https://doi.org/10.1161/HYPERTENSIONAHA.107.092403
LeBrasseur, Nathan K ; Duhaney, Toni Ann S ; De Silva, Deepa S. ; Cui, Lei ; Ip, Peter C. ; Joseph, Lija ; Sam, Flora. / Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. In: Hypertension. 2007 ; Vol. 50, No. 3. pp. 489-496.
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