Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression.
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. Western blot showed that temocapril enhanced cytosolic redox regulatory protein TRX expression, but neither mitochondrial TRX2 nor antioxidant enzymes, such as copper-zinc superoxide dismutase (Cu/Zn-SOD) or manganese superoxide dismutase (Mn-SOD) expression, was increased by the preconditioning treatment. In rats with experimental autoimmune myocarditis (EAM), the protein carbonyl content, a marker of cellular protein oxidation, was increased accompanied with enhanced TRX expression. An immunohistochemical study showed that TRX stain was enhanced in infiltrating inflammatory cells and in damaged myocytes. The severity of the myocarditis and the protein carbonyl contents were less increased in temocapril treatment (10 mg/kg/day, orally) from day 1 to day 21 in which TRX was up regulated when the inflammation started, but not in temocapril treatment from day 15-21 in which TRX was not up-regulated when the inflammation started. 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 increase in a preconditioning manner, although the mechanism of TRX induction by temocapril remains to be elucidated.
Yuan
Zuyi
Z
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kishimoto
Chiharu
C
Shioji
Keisuke
K
Nakamura
Hajime
H
Yodoi
Junji
J
Sasayama
Shigekake
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy*; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D009205:Myocarditis / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D013552:Swine; D013841:Thiazepines / Q000494:pharmacology*; D013879:Thioredoxins / Q000096:biosynthesis*; D013997:Time Factors; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D013841:Thiazepines; D013879:Thioredoxins; C055603:temocapril hydrochloride; D013482:Superoxide Dismutase; D010100:Oxygen