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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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ALA treatment decreased the TGF-β,α-SMA, and TIMP-2 expression and increased cardiac active- and pro- MMP-2 levels. The protein expression of TGF-β (A), α-SMA (B), and TIMP-2 (C) were determined by Western blot with specific antibodies as indicated, β-Actin was used as loading control. Cardiac active- and pro- MMP-2 (D/E) levels were assayed by zymogram. 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 4: ALA treatment decreased the TGF-β,α-SMA, and TIMP-2 expression and increased cardiac active- and pro- MMP-2 levels. The protein expression of TGF-β (A), α-SMA (B), and TIMP-2 (C) were determined by Western blot with specific antibodies as indicated, β-Actin was used as loading control. Cardiac active- and pro- MMP-2 (D/E) levels were assayed by zymogram. 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 evaluate the role of ALA in maintaining extracellular matrix homeostatsis and the preventing cardiac fibrosis, TGF-beta, α-SMA and TIMP-2 were determined as marker of ECM synthesis, while MMP-2 was assayed as an indicator of ECM degradation. STZ-treated diabetic rats had significantly increased LV expression of TGF-βand α-SMA (Figure 4A, 4B), consistent with enhanced ECM synthesis contributing to the increase in cardiac collagen concentration (Figure 2). ALA treatment for 11 weeks significantly decreased LV expression of TGF-β and α-SMA in the diabetic rats, but had no effect on their expression in control rats. As indicator of extracellular matrix degradation, TIMP-2 was shown to be significantly increased in STZ-induced diabetic rats (Figure 4C), consistent with significantly decreased cardiac gelatinolytic activity of active- and pro- MMP-2 levels (Figure 4D) similarly, there was a marked decrease in gelatinolytic activity of active MMP-2 levels (Figure 4E, active MMP-2/Pro-MMP-2). There was no change in the MMP-9 expression and activity in the heart tissues of diabetic rats (data not shown). ALA treatment was able to significantly decrease LV TIMP-2 expression and MMP-2 gelatinolytic activity, but had no markedly effects on basal LV TIMP-2 expression or MMP-2 gelatinolytic activity over the 11 weeks treatment period.


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 treatment decreased the TGF-β,α-SMA, and TIMP-2 expression and increased cardiac active- and pro- MMP-2 levels. The protein expression of TGF-β (A), α-SMA (B), and TIMP-2 (C) were determined by Western blot with specific antibodies as indicated, β-Actin was used as loading control. Cardiac active- and pro- MMP-2 (D/E) levels were assayed by zymogram. 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 4: ALA treatment decreased the TGF-β,α-SMA, and TIMP-2 expression and increased cardiac active- and pro- MMP-2 levels. The protein expression of TGF-β (A), α-SMA (B), and TIMP-2 (C) were determined by Western blot with specific antibodies as indicated, β-Actin was used as loading control. Cardiac active- and pro- MMP-2 (D/E) levels were assayed by zymogram. 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 evaluate the role of ALA in maintaining extracellular matrix homeostatsis and the preventing cardiac fibrosis, TGF-beta, α-SMA and TIMP-2 were determined as marker of ECM synthesis, while MMP-2 was assayed as an indicator of ECM degradation. STZ-treated diabetic rats had significantly increased LV expression of TGF-βand α-SMA (Figure 4A, 4B), consistent with enhanced ECM synthesis contributing to the increase in cardiac collagen concentration (Figure 2). ALA treatment for 11 weeks significantly decreased LV expression of TGF-β and α-SMA in the diabetic rats, but had no effect on their expression in control rats. As indicator of extracellular matrix degradation, TIMP-2 was shown to be significantly increased in STZ-induced diabetic rats (Figure 4C), consistent with significantly decreased cardiac gelatinolytic activity of active- and pro- MMP-2 levels (Figure 4D) similarly, there was a marked decrease in gelatinolytic activity of active MMP-2 levels (Figure 4E, active MMP-2/Pro-MMP-2). There was no change in the MMP-9 expression and activity in the heart tissues of diabetic rats (data not shown). ALA treatment was able to significantly decrease LV TIMP-2 expression and MMP-2 gelatinolytic activity, but had no markedly effects on basal LV TIMP-2 expression or MMP-2 gelatinolytic activity over the 11 weeks treatment period.

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