Tissue kallikrein and kinin infusion rescues failing myocardium after myocardial infarction.
BACKGROUND
Tissue kallikrein is a serine proteinase that generates the vasoactive kinin peptide, which produces vasodilatory, angiogenic, and antiapoptotic effects. In this study, we investigated the effect of a stable supply of kallikrein and kinin on ventricular remodeling and blood vessel growth in rats after myocardial infarction.


RESULTS
At 1 week after coronary artery ligation, tissue kallikrein or kinin was infused through a minipump for 4 weeks. At 5 weeks after myocardial infarction, kallikrein and kinin infusion significantly improved cardiac contractility and reduced diastolic dysfunction without affecting systolic blood pressure. Kallikrein and kinin infusion significantly increased capillary density in the noninfarcted region. Kallikrein and kinin infusion also reduced heart weight/body weight ratio, cardiomyocyte size, and atrial natriuretic peptide and brain natriuretic peptide expression in the noninfarcted area. Moreover, kallikrein and kinin infusion inhibited interstitial collagen deposition, collagen fraction volume, and collagen I and collagen III mRNA levels, transforming growth factor (TGF)-beta1 and plasminogen activator inhibitor-1 expression, and Smad2 phosphorylation. The effects of kallikrein and kinin on cardiac remodeling were associated with increased nitric oxide levels and reduced NADPH oxidase expression and activity, superoxide formation, and malondialdehyde levels. Furthermore, in cultured cardiac fibroblasts, kinin inhibited angiotensin II-stimulated TGF-beta1 production, and the effect was blocked by icatibant.


CONCLUSIONS
These results indicate that a subdepressor dose of kallikrein or kinin can restore impaired cardiac function in rats with postinfarction heart failure by inhibiting hypertrophy and fibrosis and promoting angiogenesis through increased nitric oxide formation and suppression of oxidative stress and TGF-beta1 expression.
Yao
Yu-Yu
YY
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Yin
Hang
H
Shen
Bo
B
Chao
Lee
L
Chao
Julie
J
D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000209:etiology*; D006332:Cardiomegaly / Q000517:prevention & control; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007260:Infusion Pumps; D007705:Kinins / Q000008:administration & dosage / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016879:Salvage Therapy; D020840:Tissue Kallikreins / Q000008:administration & dosage / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects