Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression.
OBJECTIVE
Thioredoxin (TRX) is a redox regulatory protein that protects cells from various stresses. Angiotensin-converting enzyme (ACE) inhibitor was reported to enhance endogenous antioxidant enzyme activities. This study was carried out to investigate whether temocapril, a novel non-sulfhydryl-containing ACE inhibitor, reduces the severity of myocarditis via redox regulation mechanisms involving TRX.


RESULTS
In normal rat myocytes in vitro and in vivo, Western blot showed that temocapril enhanced cytosolic redox regulatory protein TRX expression, but that neither mitochondrial TRX2 nor antioxidant enzymes, such as copper-zinc superoxide dismutase (Cu/Zn-SOD) or manganese superoxide dismutase (Mn-SOD) expression, was up-regulated by the preconditioning treatment. In rats with experimental autoimmune myocarditis (EAM), the severity of myocarditis and the protein carbonyl contents were less increased in temocapril treatment (10 mg/kg/day, orally) from day 1 to day 21, but not in temocapril treatment from day 15 to day 21. An immunohistochemical study showed that TRX stain was enhanced in infiltrating inflammatory cells and in damaged myocytes. Considering the characteristics of this model that myocardial inflammation begins around day 15 and increases until day 21, temocapril treatment for 3 weeks might be thought of as a preconditioning treatment.


CONCLUSIONS
The results suggest that TRX and the redox state modified by TRX may play a crucial role in the pathophysiology of EAM. Temocapril ameliorates myocarditis associated with inducing TRX up-regulation in a preconditioning manner, although the mechanism of TRX up-regulation by temocapril remains to be elucidated.
Yuan
Zuyi
Z
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Kishimoto
Chiharu
C
Shioji
Keisuke
K
Nakamura
Hajime
H
Yodoi
Junji
J
Sasayama
Shigekake
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins; D008565:Membrane Proteins / Q000378:metabolism; D009205:Myocarditis / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013482:Superoxide Dismutase / Q000378:metabolism; D013841:Thiazepines / Q000627:therapeutic use*; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D013841:Thiazepines; D014157:Transcription Factors; C063460:Trl protein, Drosophila; C516042:Trx-2 protein, Drosophila; C516113:Txn2 protein, rat; D013879:Thioredoxins; C055603:temocapril hydrochloride; D013482:Superoxide Dismutase