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L-arginine reduces heart collagen accumulation in the diabetic db/db mouse
Insights
L-arginine supplementation significantly reduced collagen accumulation in the hearts of diabetic mice, suggesting a potential therapeutic role in managing diabetic cardiomyopathy by targeting collagen cross-linking.
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Biochemistry
Background:
- Diabetic cardiomyopathy is characterized by excessive collagen buildup in the heart.
- This fibrosis is linked to abnormal collagen cross-linking and increased collagen production.
- Previous research showed L-arginine reduced kidney collagen in diabetic mice.
Purpose of the Study:
- To investigate the effect of L-arginine on cardiac fibrosis in diabetic mice.
- To determine if L-arginine can mitigate collagen accumulation in the heart.
Main Methods:
- Spontaneously diabetic mice (db/db) were treated with L-arginine for 4 months.
- Key parameters measured included total heart collagen, collagen solubility, and markers of glycation and oxidative stress.
- Glycemic control was monitored using blood glucose and fructosamine levels.
Main Results:
- L-arginine treatment significantly reduced total collagen content in heart tissue (P = .0001).
- Collagen from L-arginine treated hearts showed increased acid solubility (P = .02).
- No significant differences were observed in carboxymethyllysine, O-tyrosine, or glycemic control parameters between groups.
Conclusions:
- L-arginine effectively reduces total heart collagen and increases its solubility, supporting the cross-linking hypothesis.
- The results suggest L-arginine may act by blocking reactive carbonyl groups, similar to aminoguanidine.
- While L-arginine impacts collagen directly, the correlation with glycemic control highlights glucose's role in collagen metabolism.
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.