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

Abstract

IntroductionRecent 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).MethodsAIA 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.ResultsCompared 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.ConclusionCollectively, 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.

Cardiomyopathy, oxidative stress and impaired contractility in a rheumatoid arthritis mouse model

“…Tgf-β is a key signalling peptide that mediates fibrogenesis by activating cardiac fibroblasts, which promote deposition of extracellular matrix proteins such as collagen 1 19. We found that the hearts of mice subjected to CAIA display profibrogenic signalling as the gene expression of Tgf-β and collagen 1 was increased, which corroborates previous literature showing increased cardiac fibrosis and oxidative stress in a rat model of arthritis 20. Fibrogenesis signalling can be triggered by a range of stimuli with chronic inflammation being one typical stimulus.…”

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

“…Serum and left ventricular tissues from rats with adjuvant induced arthritis (AIA), an animal model of rheumatoid arthritis, had a higher concentration of oxidative stress related aldehyde than controls 40. NADPH and glutathione pools were 30% lower in left ventricular tissues of AIA rats than controls, suggesting depletion of key antioxidant system reserves related to inflammatory arthritis.…”

In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice

“…Blood was centrifuged at 3,000 rpm for 10 min, and serum samples were stored at -80°C before use. 36 Articular tissues (0.1 g) were harvested in 0.5 mL lysis buffer and processed by Precellys 24 Homogenizer, according to the manufacturer's instructions. Homogenized tissues were centrifuged and the supernatants preserved and stored at -80°C.…”