Circulation, Vol 90, 479-483, Copyright © 1994 by American Heart Association
A Khaidar, M Marx, B Lubec and G Lubec
BACKGROUND: Diabetic cardiomyopathy presents with significant collagen
accumulation; decreased solubility, increased glucose-mediated abnormal
cross-linking, free radical cross-linking, or glucose-induced increased
transcription of collagen is incriminated. In a previous study, we reduced
collagen accumulation in the kidneys of diabetic mice by treatment with
oral arginine. This observation led us to examine the effect of arginine on
cardial fibrosis. METHODS AND RESULTS: Twenty- nine db/db spontaneously
diabetic mice were used in the experiments. Sixteen were given L-arginine
(free base, in tap water, 50 mg/kg body wt per day) for 4 months. At the
end of the experiment, we determined total collagen content of total
ventricular tissue, acid solubility, carboxymethyllysine, O-tyrosine,
glutathione, blood glucose, and fructosamine as parameters for glycemic
control. Heart collagen level was significantly (P = .0001) reduced in the
experimental group (mean, 0.24 +/- 0.05) compared with the control group
(mean, 0.49 +/- 0.10 mumol hydroxyproline per 100 mg heart tissue).
Significantly more collagen could be eluted from heart samples of the
experimental group (P = .02). Carboxymethyllysine and O-tyrosine did not
differ when related to heart weight. Glutathione level was significantly
higher in the untreated group (P = .003). Parameters of glycemic control
did not differ between the groups. CONCLUSIONS: Our findings clearly
indicate that L-arginine reduced total heart collagen and increased acid
solubility of heart collagen. Both findings are compatible with the
cross-linking hypothesis. The data for carboxymethyllysine, O-tyrosine, and
glutathione would rule out the glycoxidation hypothesis and, therefore,
free radical cross-linking. The postulated mechanism of action is most
likely the blocking of reactive carbonyl functions by L- arginine in
analogy to aminoguanidine activity. Correlations of collagen with glycemic
control, however, point to an association of glucose with collagen
metabolism, a phenomenon documented in cell cultures at the transcriptional
level.
ARTICLES
L-arginine reduces heart collagen accumulation in the diabetic db/db mouse
Department of Paediatrics, University of Vienna, Austria.
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