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


CONCLUSIONS
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.
Qin
Q
Shi
Jamilah
J
Abusarah
Ghayath
G
Baroudi
Julio C
JC
Fernandes
Hassan
H
Fahmi
Mohamed
M
Benderdour
D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017257:Ramipril / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000447:Aldehydes; D000806:Angiotensin-Converting Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; C027576:4-hydroxy-2-nonenal; D015232:Dinoprostone; D017257:Ramipril