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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

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

View larger version (21K): [in a new window]   Figure 1 Time-related changes in systolic blood pressure of uni-nephrectomized control rats (UN control) (n = 6), deoxycorticosterone acetate-salt rats treated with vehicle (DOCA-V) (n = 7), and deoxycorticosterone acetate-salt rats treated with fenofibrate (DOCA-F) (n = 8) rats. Data are expressed as the mean value ± SEM. **p < 0.01 vs. UN control.

View larger version (121K): [in a new window]   Figure 2 Interstitial and perivascular collagen deposition in the myocardial region of the left ventricle, as demonstrated by Masson trichrome staining. (a, b) UN control; (c, d) DOCA-V; and (e, f) DOCA-F. Bar indicates 500 µm (left) or 100 µm (right). Abbreviations as in Figure 1.

View larger version (28K): [in a new window]   Figure 3 Effects of peroxisome proliferators-activated receptor-alpha activator on the hydroxyproline content and procollagen messenger ribonucleic acid (mRNA) expression in DOCA-salt hypertensive rats. The hydroxyproline content (A) and expression of procollagen I (B) and III (C) mRNA levels are compared among the three groups: UN control (n = 6), DOCA-V (n = 7), and DOCA-F (n = 8). Expression of mRNA was determined by reverse-transcription polymerase chain reaction, and procollagen mRNA expression was corrected by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The DOCA-F results are compared with UN control or DOCA-V and shown as the mean value ± SEM. *p < 0.05 vs. UN control, **p < 0.01 vs. UN control, p < 0.05 vs. DOCA-V. Abbreviations as in Figure 1.

View larger version (26K): [in a new window]   Figure 4 Effects of peroxisome proliferators-activated receptor-alpha activator on messenger ribonucleic acid (mRNA) expression of interleukin (IL)-6 (A), cyclooxygenase (COX)-2 (B), vascular cell adhesion molecule (VCAM)-1 (C), and monocyte chemoattractant protein (MCP)-1 (D) in the left ventricle of deoxycorticosterone acetate-salt hypertensive rats. For each, the mRNA levels are compared among three groups: UN control (n = 6), DOCA-V (n = 7), and DOCA-F (n = 8). Each column and bar represent the mean value ± SEM. *p < 0.05 vs. UN control, **p < 0.01 vs. UN control, p < 0.05 vs. DOCA-V, p < 0.01 vs. DOCA-V. Abbreviations as in Figure 1.

View larger version (27K): [in a new window]   Figure 5 Effects of peroxisome proliferators-activated receptor-alpha activator on nuclear factor (NF)-kappa-B activation and I-kappa-B-alpha expression in deoxycorticosterone acetate-salt hypertensive rats. (A) The NF-kappa-B binding activity in the left ventricle of deoxycorticosterone acetate-salt rats. Binding specificity was assessed using an ELISA-based format, as described in the Methods. Absorbance was measured at 655 nm. Data are expressed as the mean value ± SEM. *p < 0.05 vs. UN control, p < 0.05 vs. DOCA-V. (B) Representative Western blots of I-kappa-B-alpha protein in the left ventricle of UN control, DOCA-V, and DOCA-F rats. Abbreviations as in Figure 1.