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Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid.

Li CJ, Lv L, Li H, Yu DM - Cardiovasc Diabetol (2012)

Bottom Line: After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation.To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated.These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.

ABSTRACT

Background: Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model.

Methods: Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot.

Results: DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation.

Conclusions: These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.

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Related in: MedlinePlus

ALA Reduces diabetes-induced myocardial activation of JNK and P38. Total protein was obtained from the hearts of STZ-induced diabetic rats and vehicle rats. Phosphorylated and total JNK, P38 and ERK were determined by Western blot with specific antibodies as indicated. The extent of JNK (A), P38 (B) and ERK (C) phosphorylation was quantified by phosphorylated protein/total protein. Representative image, bar graph, density analysis results from 8 hearts per group. Data represent mean ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group.
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Figure 5: ALA Reduces diabetes-induced myocardial activation of JNK and P38. Total protein was obtained from the hearts of STZ-induced diabetic rats and vehicle rats. Phosphorylated and total JNK, P38 and ERK were determined by Western blot with specific antibodies as indicated. The extent of JNK (A), P38 (B) and ERK (C) phosphorylation was quantified by phosphorylated protein/total protein. Representative image, bar graph, density analysis results from 8 hearts per group. Data represent mean ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group.

Mentions: To further assess the signaling pathways potentially involved in the cardiac remodeling process induced by diabetes, we examined key components of the MAPK pathways in the treatment groups. As shown in Figure 5, there was marked increase the JNK (Figure 5A) and p38 MAPK (Figure 5B) activation in the heart tissues of diabetic rats compared to the NC group, ALA treatment of diabetic rats for 11 weeks significantly mitigated JNK and p38 MAPK activation. There was no change in the ERK activation in the heart tissues of diabetic rats compared to the NC group; and ALA treatment of diabetic rats has no significant effect on ERK activation (Figure 5C).


Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid.

Li CJ, Lv L, Li H, Yu DM - Cardiovasc Diabetol (2012)

ALA Reduces diabetes-induced myocardial activation of JNK and P38. Total protein was obtained from the hearts of STZ-induced diabetic rats and vehicle rats. Phosphorylated and total JNK, P38 and ERK were determined by Western blot with specific antibodies as indicated. The extent of JNK (A), P38 (B) and ERK (C) phosphorylation was quantified by phosphorylated protein/total protein. Representative image, bar graph, density analysis results from 8 hearts per group. Data represent mean ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472273&req=5

Figure 5: ALA Reduces diabetes-induced myocardial activation of JNK and P38. Total protein was obtained from the hearts of STZ-induced diabetic rats and vehicle rats. Phosphorylated and total JNK, P38 and ERK were determined by Western blot with specific antibodies as indicated. The extent of JNK (A), P38 (B) and ERK (C) phosphorylation was quantified by phosphorylated protein/total protein. Representative image, bar graph, density analysis results from 8 hearts per group. Data represent mean ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group.
Mentions: To further assess the signaling pathways potentially involved in the cardiac remodeling process induced by diabetes, we examined key components of the MAPK pathways in the treatment groups. As shown in Figure 5, there was marked increase the JNK (Figure 5A) and p38 MAPK (Figure 5B) activation in the heart tissues of diabetic rats compared to the NC group, ALA treatment of diabetic rats for 11 weeks significantly mitigated JNK and p38 MAPK activation. There was no change in the ERK activation in the heart tissues of diabetic rats compared to the NC group; and ALA treatment of diabetic rats has no significant effect on ERK activation (Figure 5C).

Bottom Line: After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation.To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated.These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.

ABSTRACT

Background: Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model.

Methods: Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot.

Results: DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation.

Conclusions: These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.

Show MeSH
Related in: MedlinePlus