Ramipril attenuates lipid peroxidation and cardiac fibrosis in an experimental model of rheumatoid arthritis

Qin Shi, Jamilah Abusarah, Ghayath Baroudi, Julio C Fernandes, Hassan Fahmi, Mohamed Benderdour, Qin Shi, Jamilah Abusarah, Ghayath Baroudi, Julio C Fernandes, Hassan Fahmi, Mohamed Benderdour

Abstract

Introduction: Recent studies revealed that co-morbidity and mortality due to cardiovascular disease are increased in patients with rheumatoid arthritis (RA) but little is known about factors involved in these manifestations. This study aimed at characterizing the impact of arthritis on oxidative stress status and tissue fibrosis in the heart of rats with adjuvant-induced arthritis (AIA).

Methods: AIA was induced with complete Freund's adjuvant in female Lewis rats. Animals were treated by oral administration of vehicle or angiotensin-converting enzyme inhibitor ramipril (10 mg/kg/day) for 28 days, beginning 1 day after arthritis induction. Isolated adult cardiomyocytes were exposed to 10 μM 4-hydroxynonenal (HNE) for 24 hours in the presence or absence of 10 μM ramipril.

Results: Compared to controls, AIA rats showed significant 55 and 30% increase of 4-HNE/protein adducts in serum and left ventricular (LV) tissues, respectively. Cardiac mitochondrial NADP+-isocitrate dehydrogenase (mNADP-ICDH) activity decreased by 25% in AIA rats without any changes in its protein and mRNA expression. The loss of mNADP-ICDH activity was correlated with enhanced accumulation of HNE/mNADP-ICDH adducts as well as with decrease of glutathione and NADPH. Angiotensin II type 1 receptor (AT1R) expression and tissue fibrosis were induced in LV tissues from AIA rats. In isolated cardiomyocytes, HNE significantly decreased mNADP-ICDH activity and enhanced type I collagen and connective tissue growth factor expression. The oral administration of ramipril significantly reduced HNE and AT1R levels and restored mNADP-ICDH activity and redox status in LV tissues of AIA rats. The protective effects of this drug were also evident from the decrease in arthritis scoring and inflammatory markers.

Conclusion: Collectively, our findings disclosed that AIA induced oxidative stress and fibrosis in the heart. The fact that ramipril attenuates inflammation, oxidative stress and tissue fibrosis may provide a novel strategy to prevent heart diseases in RA.

Figures

Figure 1
Figure 1
Pro-inflammatory cytokines determination and clinical evaluation of adjuvant-induced arthritis (AIA). (A) Tumor necrosis factor-alpha (TNFα) and (B) prostaglandin E2 (PGE2) were assessed in serum from control and AIA rats with ELISA. (C-E) Clinical evaluation was performed by measuring paw swelling (C, D) and arthritis score (C, E). Data are mean ± SEM of three experiments. Statistics: one-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001 (CTL versus AIA), #P < 0.05 (AIA versus AIA+Ram). CTL, control; Ram, ramipril.
Figure 2
Figure 2
Quantification and characterization of 4-hydroxynonenal (HNE)/protein adducts by enzyme-linked immunosorbent assay (ELISA) and Western blotting. (A) HNE/protein adducts were measured by ELISA in serum and left ventricular (LV) tissues from control and adjuvant-induced arthritis (AIA) rats (n = 6). (B) HNE/protein adducts were characterized by Western blotting in total proteins of LV tissues from control and AIA rats. Values are the mean ± SEM of three experiments. *P < 0.05; **P < 0.01 (CTL versus AIA), #P < 0.05 (AIA versus AIA+Ram) by one-way ANOVA. CTL, control; Ram, ramipril.
Figure 3
Figure 3
Cardiac mitochondrial NADP+-dependent isocitrate dehydrogenase (mNADP-ICDH) activity (A), protein (B), and mRNA (C). Total proteins and RNA were extracted from left ventricular (LV) tissues of control and adjuvant-induced arthritis (AIA) rats and processed to enzymatic assay (A), Western blotting (B) or real-time PCR (C), as described under Materials and Methods. (D) Cardiac 4-hydroxynonenal (HNE)/NADP-ICDH adducts were identified in total proteins by immunoprecipitation as described in Material and Methods. Values are the mean ± SEM of three experiments. **P < 0.01 (CTL versus AIA), #P < 0.05, &P < 0.01 (AIA versus AIA+Ram) by one-way ANOVA. CTL, control; Ram, ramipril.
Figure 4
Figure 4
Determination of cardiac redox status. Glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) were determined in total proteins extracted in left ventricular (LV) tissues from control and adjuvant-induced arthritis (AIA) rats. Data are mean ± SEM of three experiments and expressed as GSSG/(GSSG+GSH) and NADP/(NADP+NADPH) ratio. Statistics: one-way ANOVA; *P < 0.05 (CTL versus AIA), #P < 0.05 (AIA versus AIA+Ram). CTL, control; Ram, ramipril.
Figure 5
Figure 5
Measurement of cardiac remodeling in left ventricular (LV) tissues from control and adjuvant-induced arthritis (AIA) rats. (A, B) Expression of angiotensin II type I receptor (AT1R) LV from AIA rats. Total proteins and RNA were extracted in LV tissues of control and AIA rats and processed to AT1R protein (A) and mRNA (B) determination by Western blotting and real-time PCR, respectively. (C) Cardiac collagen content in LV tissues was detected by the picosirius red polarization method. Histological sections obtained from control and AIA rats were stained with picosirius red solution and examined under circularly polarized light to visualize interstitial collagen by its red coloration. Surface staining for collagen was calculated as a percentage of the total surface. Values are the mean ± SEM of three experiments. **P < 0.01, ***P < 0.001 (CTL versus AIA), #P < 0.05, &P < 0.01 (AIA versus AIA+Ram) by one-way ANOVA. CTL, control; Ram, ramipril.
Figure 6
Figure 6
Modulation of mitochondrial NADP+-dependent isocitrate dehydrogenase (mNADP-ICDH), type I collagen (Col I) and connective tissue growth factor (CTGF) in isolated adult rat cardiomyocytes. Cells were treated with 10 μM 4-hydroxynonenal (HNE) for 48 hours in the presence or absence of 10 μM ramipril and then total proteins were preceded to the determination of (A) NADP-ICDH activity, (B) HNE/NADP-ICDH adducts, and (C) Col I and CTGF protein as described in Materials and Methods. Values are the mean ± SEM of three experiments. *P < 0.05, ***P < 0.001 (CTL versus HNE), #P < 0.05, &P < 0.01 (HNE versus HNE+Ram) by one-way ANOVA. CTL, control; Ram, ramipril.

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