Nonclassical Axis of the Renin-Angiotensin System and Neprilysin: Key Mediators That Underlie the Cardioprotective Effect of PPAR-Alpha Activation during Myocardial Ischemia in a Metabolic Syndrome Model

Figures

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  Figure 1. Effect of fenofibrate on the expression of renin-angiotensin-converting enzyme (ACE) and ACE2. The expression was evaluated in the left ventricles from the control (CT) and metabolic syndrome (MetS) rats subjected to sham (Sh) or myocardial infarction (MI) and treated for two weeks with either vehicle (V) or fenofibrate (F). (a) Representative western blot analysis. (b) ACE protein expression. (c) ACE2 protein expression. Data represent mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Δp < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; #p < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V. Analysis of variance-Newman-Keuls.

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  Figure 2. Effect of fenofibrate on angiotensin II and angiotensin-(1-7) levels. (a) Angiotensin II and (b) angiotensin-(1-7) concentrations were determined in the homogenate from myocardial ischemic areas from the sham (Sh), myocardial infarction (MI) vehicle-treated, and MI fenofibrate-treated experimental groups. The values show the mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Δp < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; #p < 0.05 vs. CT-MI-V; ωp < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V; Ψp < 0.05 vs. CT-MI-F. Analysis of variance-Newman-Keuls.

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  Figure 3. Expression of cardiac angiotensin receptors. The proteins were evaluated in the left ventricles from the control (CT) and metabolic syndrome (MetS) rats subjected to sham (Sh) or myocardial infarction (MI) and treated for two weeks with either vehicle (V) or fenofibrate (F). (a) Representative immunoblot. (b) Angiotensin II-type 1 receptor (AT1R) protein expression. (c) Angiotensin II-type 2 receptor (AT2R) protein expression. (d) MasR protein expression. The values show the mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Δp < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; #p < 0.05 vs. CT-MI-V; ωp < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V; Ψp < 0.05 vs. CT-MI-F. Analysis of variance-Newman-Keuls.

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  Figure 4. Effect of fenofibrate on the expression of aminopeptidase A (APA) and angiotensin III (Ang III) concentrations in the control (CT) and metabolic syndrome (MetS) rats under ischemic conditions (MI). (a) Representative western blot analysis. (b) APA protein expression. (c) Ang III concentration. Arbitrary units (AU). The values show the mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; ωp < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V. Analysis of variance-Newman-Keuls.

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  Figure 5. Effect of fenofibrate administration on myocardial aminopeptidase N (APN) expression in myocardial tissue from the control (CT) and metabolic syndrome (MetS) animals. (a) Representative image. (b) Angiotensin IV concentration. (c) Insulin-regulated aminopeptidase (IRAP) protein expression. The values show the mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Δp < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; #p < 0.05 vs. CT-MI-V; ωp < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V. Analysis of variance-Newman-Keuls.

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  Figure 6. Effect of fenofibrate on the expression of neprilysin (NEP) and bradykinin concentration in control and under ischemic conditions. (a) Representative western blot analysis. (b) NEP protein expression. (c) Bradykinin concentration. The values show the mean ± SEM (n = 5 per group). ∗p < 0.05 vs. CT-Sh; Δp < 0.05 vs. CT-Sh; Σp < 0.05 vs. MetS-Sh; #p < 0.05 vs. CT-MI-V; ωp < 0.05 vs. CT-MI-V; &p < 0.05 vs. MetS-MI-V. Analysis of variance-Newman-Keuls.

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  Figure 7. Fenofibrate treatment decreased the area at risk in myocardial infarcted rats. Representative images of TTC staining. Blue areas indicate viable tissue; the red-colored region represents tissue at risk, and the white regions indicate the infarcted myocardium. CT-Sh and MetS-Sh: control and metabolic syndrome sham-operated groups; CT-MI-V: control myocardial infarction vehicle-treated; CT-MI-F: control myocardial infarction fenofibrate-treated; MetS-MI-V: metabolic syndrome myocardial infarction vehicle-treated; MetS-MI-F: metabolic syndrome myocardial infarction fenofibrate-treated.