Fenofibrate as a Modulator of the Renin–Angiotensin System in Su/Hx-Induced Pulmonary Arterial Hypertension

Figures

• 

  Figure 1. Fenofibrate attenuates the development of Su/Hx-induced PAH. (A) Right ventricular systolic pressure (RVSP), (B) mean pulmonary artery pressure (mPAP), (C) right ventricular hypertrophy. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. *** p < 0.001, **** p < 0.0001 vs. Control; Δ p < 0.05, ΔΔ p < 0.01, ΔΔΔΔ p < 0.0001 vs. Su/Hx.

• 

  Figure 2. Fenofibrate attenuates thickening of the medial wall of pulmonary arterioles. Representative micrographs of immunohistochemical labeling of actin myofilaments of smooth muscle cells that constitute the medial arterioles’ wall. Compared to the control group, SuHx-treated rats exhibit medial layer thickening and a narrowed lumen; the medial layer is thinner in SuHx rats with FF administration. This difference was confirmed by morphometry, which showed significantly less widening of the arterioles’ muscular wall in the Su/Hx + FF rats than in Su/Hx rats. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. n = 3. **** p < 0.0001 vs. Control; ΔΔ p < 0.01 vs. Su/Hx.

• 

  Figure 3. Fenofibrate improves pulmonary hemodynamic parameters in PAH. (A) Systolic pulmonary artery pressure (SPAP), (B) pulmonary artery effective elastance. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. ** p < 0.01, *** p < 0.001 vs. Control; Δ p < 0.05, ΔΔ p < 0.01 vs. Su/Hx.

• 

  Figure 4. Fenofibrate modulates renin–angiotensin system components in lung tissue in PAH. (A) Angiotensin II (Ang II) concentrations. (B) Angiotensin (1–7) (Ang (1–7)) concentrations. (C) Ang II/Ang (1–7) ratio. (D) Angiotensin-converting enzyme 2 (ACE2) concentrations. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. * p < 0.05, ** p < 0.01, **** p < 0.0001 vs. Control; ΔΔΔΔ p < 0.0001 vs. Su/Hx.

• 

  Figure 5. Fenofibrate effect on renin–angiotensin system components in lung tissue in PAH. Representative micrographs of renin–angiotensin system components detected by immunohistochemistry. They showed the positive area in pulmonary tissue comparing the Su/Hx and Su/Hx + FF experimental groups. The indicated molecules were highly expressed, particularly in the endothelial cells of hypertrophic arterioles in the Su/Hx + FF group, except for angiotensin II receptor type 1 (AT1R), which was more abundant in the Su/Hx group. (All micrographs 200×magnification). MAS: receptor for the angiotensin-(1–7); ACE2: Angiotensin-converting enzyme 2. ΔΔ p < 0.01, ΔΔΔΔ p < 0.0001 vs. Su/Hx.

• 

  Figure 6. Fenofibrate preserves nitrate (NO3−) and nitrite (NO2−) concentrations in lung tissue. (A) NO3− concentrations in lung tissue. (B) NO2− concentrations in the lung tissue. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. * p < 0.05 vs. Control; Δ p < 0.05 vs. Su/Hx.

• 

  Figure 7. Fenofibrate partially preserves Bmpr2 and Smad5 expression in lung tissue in PAH. (A) Bone morphogenetic protein receptor type 2 (Bmpr2) gene expression levels. (B) Mothers against decapentaplegic homolog 5 (Smad5) gene expression levels. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. ** p < 0.01 vs. Control.

• 

  Figure 8. Fenofibrate improves right ventricular function in PAH. (A) Right ventricular diastolic pressure, (B) right ventricular developed pressure, (C) right ventricle–pulmonary artery coupling index, and (D) maximal and minimal rates of pressure change (dp/dt max and dp/dt min) in the right ventricle. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. Control; Δ p < 0.05, ΔΔ p < 0.01 vs. Su/Hx.

• 

  Figure 9. Fenofibrate modulates renin–angiotensin system components in the right ventricle in PAH. (A) Angiotensin II (Ang II) concentrations. (B) Angiotensin (1–7) (Ang (1–7)) concentrations. (C) Ang II/Ang (1–7) ratio. (D) Angiotensin-converting enzyme 2 (ACE2) concentrations. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. ** p < 0.01 vs. Control.

• 

  Figure 10. Fenofibrate preserves nitrate (NO3−) and nitrite (NO2−) concentrations in the right ventricle in PAH. (A) NO3− concentrations in the right ventricle. (B) NO2− concentrations in the right ventricle. Data are presented as mean ± SD. Differences were tested by one-way ANOVA followed by Tukey’s multiple comparisons post hoc test; p ≤ 0.05 was considered statistically significant. * p < 0.05, **** p < 0.0001 vs. Control; ΔΔΔΔ p < 0.0001 vs. Su/Hx.

• 

  Figure 11. Experimental design.