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.
Highlights
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
In comparison to arthritic animals, ramipril-treated rats displayed a significant decrease in serum TNFa and prostaglandin E2 (PGE2) levels
None of the indicated parameters including TNFa, PGE2 and arthritis scoring was changed in control adjuvant-induced arthritis (AIA) rats receiving dimethyl sulfoxide (DMSO) or control animals receiving ramipril alone
Summary
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. Rheumatoid arthritis (RA) is a common, systemic, autoimmune disease that leads to joint inflammation and progressive cartilage and bone erosion [1]. Premature mortality among RA patients is frequently due to cardiovascular (CV) diseases and congestive heart failure (HF) [3,4]. Given recent appreciation of the important role of inflammatory with RA [8]. In addition to their effects on blood pressure, cardiac function, and antiproteinuric effect, ACE inhibitors have anti-inflammatory and immunomodulating properties [9]. Much remains to be learned on the beneficial role of ACE inhibitors in preventing CV complications in RA patients
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