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. 2012;7(10):e45541.
doi: 10.1371/journal.pone.0045541. Epub 2012 Oct 1.

The critical role of Astragalus polysaccharides for the improvement of PPARα [ correction of PPRAα]-mediated lipotoxicity in diabetic cardiomyopathy

Wei Chen  1 , Yanping Xia, Xuelan Zhao, Hao Wang, Wenjie Chen, Maohua Yu, Yiming Li, Hongying Ye, Yu Zhang
Affiliations

The critical role of Astragalus polysaccharides for the improvement of PPARα [ correction of PPRAα]-mediated lipotoxicity in diabetic cardiomyopathy

Wei Chen et al. PLoS One. 2012.

Abstract

Background: Obesity-related diabetes mellitus leads to increased myocardial uptake and oxidation of fatty acids, resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that Astragalus polysaccharides (APS) administration was sufficient to improve the systemic metabolic disorder and cardiac dysfunction in diabetic models.

Methodology/principal findings: To investigate the precise role of APS therapy in the pathogenesis of myocardial lipotoxity in diabetes, db/db diabetic mice and myosin heavy chain (MHC)- peroxisome proliferator-activated receptor (PPAR) α mice were characterized and administrated with or without APS with C57 wide- type mice as normal control. APS treatment strikingly improved the myocyte triacylglyceride accumulation and cardiac dysfunction in both db/db mice and MHC-PPARα mice, with the normalization of energy metabolic derangements in both db/db diabetic hearts and MHC-PPARα hearts. Consistently, the activation of PPARα target genes involved in myocardial fatty acid uptake and oxidation in both db/db diabetic hearts and MHC-PPARα hearts was reciprocally repressed by APS administration, while PPARα-mediated suppression of genes involved in glucose utilization of both diabetic hearts and MHC-PPARα hearts was reversed by treatment with APS.

Conclusions: We conclude that APS therapy could prevent the development of diabetic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Echocardiographic properties and expression of cardiac dysfunction marker genes in hearts of mice.
Echocardiographic studies were performed on db/db mice and MHC-PPARα mice with or without APS administration at the age of 20 weeks, with C57 wide-type mice as normal control. (A) Representative echocardiographic images; (B) fractional shortening (FS). Expression of cardiac dysfunction marker genes encoding BNP (C), Skeletal α-actin (D) and SERCA2a (E) was determined by real-time RT-PCR analysis. The relative gene expression of db/db mice and MHC-PPARα mice was normalized to the value of C57 wide-type mice, and expressed as fold change. All groups n = 8. Bars represent means±S.E.M. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice. BNP, brain-type natriuretic peptide; SERCA2a, sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2a; MHC, myosin heavy chain; PPAR, peroxisome proliferator-activated receptor; APS, astragalus polysaccharides.
Figure 2
Figure 2. Serum biometric parameters of mice at different age.
Serum glucose, insulin, nonesterified fatty acid (FFA) and triacylglyceride (TAG) were detected in db/db mice and MHC-PPARα mice with or without APS administration at the age of 5 weeks (A) and 20 weeks (B–E) respectively, with C57 wide-type mice as normal control. All groups n = 8. Bars represent means±S.E.M. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice.
Figure 3
Figure 3. Intramyocardial lipid accumulation in mice.
Myocardial triacylglyceride levels (A) in db/db mice and MHC-PPARα mice with or without APS administration at 20 week-old were determined by ESI/MS. Mean levels of TAG-associated fatty acid with chain length of 16∶0 (B), 18∶0 (C), 18∶1 (D), and 18∶2 (E) in the hearts of each group were shown respectively. (F) representative images of myocardium stained with oil red O. All groups n = 8. Bars represent means±S.E.M. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice.
Figure 4
Figure 4. Myocardial fuel untilization in mice at the age of 20 weeks.
Basal cardiac palmitate uptake (A) and glucose uptake (B) were measured in hearts from awake db/db mice and MHC-PPARα mice with/without APS at the age of 20 weeks, with C57 mice as normal control. Free fatty acid oxidation (C) and glucose oxidation (D) were assessed in isolated working hearts from db/db mice and MHC-PPARα mice with/without APS at the age of 20 weeks, with C57 mice as normal control. All groups n = 8. Bars represent means±S.E.M. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice.
Figure 5
Figure 5. Gene expression of PPARα target genes in hearts of mice at different age.
Cardiac tissues from db/db mice and MHC-PPARα mice with/without APS administration were detected for the gene expression at the age of 5 weeks (A) and 20 weeks (B-H) respectively, with C57 mice as normal control. Myocardial mRNA levels of PPARα target genes were determined by real-time RT-PCR analysis, encoding PPARα (B), M-CPF 1(C), ACO (D), FATP 1 (E), FACS 1(F), GLUT4 (G) and PDK4 (H). The relative gene expression of db/db mice and MHC-PPARα mice was normalized to the value of C57 wide-type mice, and expressed as fold change. All groups n = 6. Bars represent means±S.E.M. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice. M-CPF1, muscle-typecarnitine palmitoyltransferase 1; ACO, acyl-CoA oxidase; FATP 1, fatty acid trasport protein-1; FACS 1, fatty acyl-CoA synthetase 1; GLUT4, glucose transporter 4; PDK4, pyruvate dehydrogenase kinase 4.
Figure 6
Figure 6. Protein levels of PPARα target genes in hearts of mice at the age of 20 weeks.
Cardiac tissues from db/db mice and MHC-PPARα mice with/without APS administration were detected for the protein expression at the age of 20 weeks, with C57 mice as normal control. Myocardial protein levels of PPARα target genes were determined by Western Blot analysis. (A) Representative autoradiographs of PPARα target genes and GAPDH (loading control) using specific antibodies. Protein levels of PPARα target genes in myocardium, encoding PPARα (B), M-CPF 1 (D), ACO (E), FATP 1(F) and FACS 1(G). PPARα activities in myocardial tissue were also determined at the end of the experiment by RIA (C). All groups n = 8. Bars represented means±S.E.M., and were corrected for GAPDH signal intensity and normalized to the value of C57 wide-type mice. *P<0.05 vs. C57 mice, # P<0.05 vs. untreated db/db mice, † P<0.05 vs. untreated MHC-PPARα mice.
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This work was supported by Chinese State Natural Science Funds Commission (Grant No: 81001568), and Shanghai Health Bureau Science Funds for Chinese Medicine (Grant No: 2010QJ033A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.