Oxidative stress causes cardiomyocyte death and subsequent
ventricular dysfunction and cardiac remodeling after
myocardial infarction (MI), thus contributing to high mortality in chronic
heart failure patients. We investigated the effects of
kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human
kallistatin gene was injected intramyocardially 20 min after
ligation of the left coronary artery. At 4 weeks after MI, expression of human
kallistatin in rat hearts was identified by reverse transcription-polymerase chain reaction, immunohistochemistry and ELISA.
Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased
myocardial infarct size and restored left ventricular wall thickness.
Kallistatin treatment significantly attenuated cardiomyocyte size and
atrial natriuretic peptide expression.
Kallistatin also reduced
collagen accumulation,
collagen fraction volume and expression of
collagen types I and III,
transforming growth factor-beta1 (TGF-beta1) and
plasminogen activator inhibitor-1 in the myocardium. Inhibition of
cardiac hypertrophy and
fibrosis by
kallistatin was associated with increased cardiac
nitric oxide (NO) levels and decreased
superoxide formation,
NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant
kallistatin inhibited intracellular
superoxide formation induced by H(2)O(2), and the
antioxidant effect of
kallistatin was abolished by Nomega-nitro-
L-arginine methyl ester (
L-NAME), indicating a NO-mediated event.
Kallistatin promoted survival of cardiomyocytes subjected to H(2)O(2) treatment, and inhibited H(2)O(2)-induced Akt and ERK phosphorylation, as well as
NF-kappaB activation. Furthermore,
kallistatin abrogated
TGF-beta-induced
collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that
kallistatin improves cardiac performance and prevents post-MI-induced
cardiac hypertrophy and
fibrosis through its
antioxidant action.