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J Am Coll Cardiol, 2004; 43:1481-1488, doi:10.1016/j.jacc.2003.11.043
© 2004 by the American College of Cardiology Foundation
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PRECLINICAL STUDIES

Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-b pathway

Takehiro Ogata, MD, PhD*, Takashi Miyauchi, MD, PhD*,*, Satoshi Sakai, MD, PhD*, Masakatsu Takanashi, PhD*, Yoko Irukayama-Tomobe, PhD* and Iwao Yamaguchi, MD, PhD*

* Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

Manuscript received August 28, 2003; revised manuscript received November 15, 2003, accepted November 18, 2003.

* Reprint requests and correspondence: Dr. Takashi Miyauchi, Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
t-miyauc{at}md.tsukuba.ac.jp

OBJECTIVES: We sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects.

BACKGROUND: Patients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis.

METHODS: Twenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uni-nephrectomized rats as normotensive controls.

RESULTS: Fenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (–dP/dtmax/P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate.

CONCLUSIONS: A PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease.

Abbreviations and Acronyms
  COX-2 = cyclooxygenase-2
  DOCA = deoxycorticosterone acetate
  DOCA-F = deoxycorticosterone acetate-salt rats treated with fenofibrate
  DOCA-V = deoxycorticosterone acetate-salt rats treated with vehicle
  ±dP/dtmax = maximum rate of left ventricular pressure rise or decline
  HF = heart failure
  IL-6 = interleukin-6
  LV = left ventricle/ventricular
  LVEDP = left ventricular end-diastolic pressure
  MCP-1 = monocyte chemoattractant protein-1
  NF = nuclear factor
  PPAR-alpha = peroxisome proliferators-activated receptor-alpha
  UN = uni-nephrectomized control
  VCAM-1 = vascular cell adhesion molecule-1




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