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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

Diabetes-induced left ventricular dysfunction were improved by ALA treatment. Cardiac dysfunction were evaluated by measuring (A) heart rate (HR), (B) left ventricular end-diastolic pressure (LVEDP), (C) maximum rate of fall of left ventricle pressure (-dP/dtmax), (D) left ventricular end-systolic pressure (LVSP), (E) maximum rate of rise of left ventricle pressure (+dP/dtmax). Eleven weeks of STZ-induced diabetes was associated with decrease in HR, LVSP and ± dp/dtmax and an increase in LVEDP, which were significantly improved by ALA treatment for 11 weeks. Results are presented as mean values ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group, n = 8 per group.
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Figure 1: Diabetes-induced left ventricular dysfunction were improved by ALA treatment. Cardiac dysfunction were evaluated by measuring (A) heart rate (HR), (B) left ventricular end-diastolic pressure (LVEDP), (C) maximum rate of fall of left ventricle pressure (-dP/dtmax), (D) left ventricular end-systolic pressure (LVSP), (E) maximum rate of rise of left ventricle pressure (+dP/dtmax). Eleven weeks of STZ-induced diabetes was associated with decrease in HR, LVSP and ± dp/dtmax and an increase in LVEDP, which were significantly improved by ALA treatment for 11 weeks. Results are presented as mean values ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group, n = 8 per group.

Mentions: To assess cardiac function, we positioned a pressure detecting catheter into the carotid artery and the LV. After 11 weeks of established diabetes, heart rate (HR) was significantly decreased in STZ group compared to the NC group. This is consistent with diabetes associated dysfunctional cardiac autonomic neuropathy. ALA treatment significantly reversed the HR to the control value. The STZ group also exhibited markedly impaired diastolic function as indicated by an increase in LVEDP and a decrease in -dp/dtmax. There was also impairment of systolic function as shown by a decrease in LVSP and +dp/dtmax. This impaired cardiac function was partially restored by ALA treatment (Figure 1).


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)

Diabetes-induced left ventricular dysfunction were improved by ALA treatment. Cardiac dysfunction were evaluated by measuring (A) heart rate (HR), (B) left ventricular end-diastolic pressure (LVEDP), (C) maximum rate of fall of left ventricle pressure (-dP/dtmax), (D) left ventricular end-systolic pressure (LVSP), (E) maximum rate of rise of left ventricle pressure (+dP/dtmax). Eleven weeks of STZ-induced diabetes was associated with decrease in HR, LVSP and ± dp/dtmax and an increase in LVEDP, which were significantly improved by ALA treatment for 11 weeks. Results are presented as mean values ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group, n = 8 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Diabetes-induced left ventricular dysfunction were improved by ALA treatment. Cardiac dysfunction were evaluated by measuring (A) heart rate (HR), (B) left ventricular end-diastolic pressure (LVEDP), (C) maximum rate of fall of left ventricle pressure (-dP/dtmax), (D) left ventricular end-systolic pressure (LVSP), (E) maximum rate of rise of left ventricle pressure (+dP/dtmax). Eleven weeks of STZ-induced diabetes was associated with decrease in HR, LVSP and ± dp/dtmax and an increase in LVEDP, which were significantly improved by ALA treatment for 11 weeks. Results are presented as mean values ± standard deviation. *p < 0.05 vs Control group, #p < 0.05 vs. STZ group, n = 8 per group.
Mentions: To assess cardiac function, we positioned a pressure detecting catheter into the carotid artery and the LV. After 11 weeks of established diabetes, heart rate (HR) was significantly decreased in STZ group compared to the NC group. This is consistent with diabetes associated dysfunctional cardiac autonomic neuropathy. ALA treatment significantly reversed the HR to the control value. The STZ group also exhibited markedly impaired diastolic function as indicated by an increase in LVEDP and a decrease in -dp/dtmax. There was also impairment of systolic function as shown by a decrease in LVSP and +dp/dtmax. This impaired cardiac function was partially restored by ALA treatment (Figure 1).

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