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.
OBJECTIVE
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/dt(max)/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.
Ogata
Takehiro
T
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Miyauchi
Takashi
T
Sakai
Satoshi
S
Takanashi
Masakatsu
M
Irukayama-Tomobe
Yoko
Y
Yamaguchi
Iwao
I
D000818:Animals; D015153:Blotting, Western; D002303:Cardiac Output, Low / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003900:Desoxycorticosterone; D003971:Diastole; D011345:Fenofibrate / Q000378:metabolism* / Q000494:pharmacology; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000378:metabolism* / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012965:Sodium Chloride / Q000009:adverse effects; D014157:Transcription Factors / Q000378:metabolism*
D000960:Hypolipidemic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D011345:Fenofibrate