Histone deacetylase inhibition of cardiac autophagy in rats on a high-fat diet with low-dose streptozotocin-induced type 2 diabetes mellitus

Ting I. Lee, Kuan Jen Bai, Yao Chang Chen, Ting Wei Lee, Cheng Chih Chung, Wen Chih Tsai, Shin Yi Tsao, Yu Hsun Kao

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Abstract

Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1(PARP1), insulin signaling, advanced glycosylation end product-specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high-fat diet (60% fat) and low-dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end-diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)-5' adenosine monophosphate-activated protein kinase α 2, light chain 3-II, Beclin-1, glucose transporter 4, p-protein kinase B, and insulin receptor substrate-1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p-mTOR-S2448, p-P70S6K-Thr-389, RAGE, tumor necrosis factor-α, and interleukin-6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

Original languageEnglish
Pages (from-to)594-601
Number of pages8
JournalMolecular Medicine Reports
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Histone Deacetylases
Autophagy
High Fat Diet
Nutrition
Streptozocin
Medical problems
Type 2 Diabetes Mellitus
Rats
Fats
Rat control
Poly Adenosine Diphosphate Ribose
Histone Deacetylase Inhibitors
Diabetes Mellitus
Proteins
Cardiomyopathies
Insulin
70-kDa Ribosomal Protein S6 Kinases
Insulin Receptor Substrate Proteins
Proto-Oncogene Proteins c-akt
Facilitative Glucose Transport Proteins

Keywords

  • Autophagy
  • Cardiomyocytes
  • Diabetes mellitus
  • Histone deacetylase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

Cite this

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title = "Histone deacetylase inhibition of cardiac autophagy in rats on a high-fat diet with low-dose streptozotocin-induced type 2 diabetes mellitus",
abstract = "Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1(PARP1), insulin signaling, advanced glycosylation end product-specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high-fat diet (60{\%} fat) and low-dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end-diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)-5' adenosine monophosphate-activated protein kinase α 2, light chain 3-II, Beclin-1, glucose transporter 4, p-protein kinase B, and insulin receptor substrate-1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p-mTOR-S2448, p-P70S6K-Thr-389, RAGE, tumor necrosis factor-α, and interleukin-6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.",
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author = "Lee, {Ting I.} and Bai, {Kuan Jen} and Chen, {Yao Chang} and Lee, {Ting Wei} and Chung, {Cheng Chih} and Tsai, {Wen Chih} and Tsao, {Shin Yi} and Kao, {Yu Hsun}",
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T1 - Histone deacetylase inhibition of cardiac autophagy in rats on a high-fat diet with low-dose streptozotocin-induced type 2 diabetes mellitus

AU - Lee, Ting I.

AU - Bai, Kuan Jen

AU - Chen, Yao Chang

AU - Lee, Ting Wei

AU - Chung, Cheng Chih

AU - Tsai, Wen Chih

AU - Tsao, Shin Yi

AU - Kao, Yu Hsun

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1(PARP1), insulin signaling, advanced glycosylation end product-specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high-fat diet (60% fat) and low-dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end-diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)-5' adenosine monophosphate-activated protein kinase α 2, light chain 3-II, Beclin-1, glucose transporter 4, p-protein kinase B, and insulin receptor substrate-1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p-mTOR-S2448, p-P70S6K-Thr-389, RAGE, tumor necrosis factor-α, and interleukin-6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

AB - Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1(PARP1), insulin signaling, advanced glycosylation end product-specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high-fat diet (60% fat) and low-dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end-diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)-5' adenosine monophosphate-activated protein kinase α 2, light chain 3-II, Beclin-1, glucose transporter 4, p-protein kinase B, and insulin receptor substrate-1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p-mTOR-S2448, p-P70S6K-Thr-389, RAGE, tumor necrosis factor-α, and interleukin-6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

KW - Autophagy

KW - Cardiomyocytes

KW - Diabetes mellitus

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