Alteration in cellular metabolism and substrate transporters in insulin resistant cardiac myocytes

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590926
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: SAOTOME Masao 浜松医科大学, 医学部・附属病院, 助教 (70509512)
• Co-Investigator(Kenkyū-buntansha): KATOH Hideki 浜松医科大学, 医学部, 助教 (80314029) ; SATOH Hiroshi 浜松医科大学, 医学部附属病院, 講師 (30293632) ; HAYASHI Hideharu 浜松医科大学, 医学部, 教授 (50135258) ; URUSHIDA Tsuyoshi 浜松医科大学, 医学部, 助教 (20334980)
• Co-Investigator(Renkei-kenkyūsha): FUNAKI Makoto 徳島大学, 医学部・附属病院, 特任教授 (10467821)
• Project Period (FY): 2009 – 2011
• Keywords: 循環器 / 高血圧 / 糖尿病

Research Abstract

In failing hearts, cardiac myocytes mainly depend on fatty acids as an energy substrate because of myocardial insulin resistance, and result in further myocardial energy deficiencies and myocardial dysfunction, namely metabolic vicious cycle. Thus, recent investigations have focused on new agents to modulate the myocardial metabolic deficiency in heart failure.
We in this study have established a novel ex vivo cardiac insulin-resistant model, focused on substrate transporters(GLUT4 and FAT/CD36), and assessed the effects of several metabolic modulators on myocardial insulin resistance. The ex vivo insulin-resistant myocytes(insulin-resistant myocytes) were produced by inducing rat H9c2 myoblasts to differentiated myocytes and culturing myocytes with saturated fatty acids(palmitate, 0. 2 mM), which mimics the increased serum fatty acid levels during heart failure. The insulin-resistant myocytes exhibited an attenuated 2-deoxy-D-glucose uptake and suppressed insulin-signaling. Also, in the insulin-resistant myocytes, GLUT4(a glucose transporter) was inhibited the insulin-mediated translocation to plasma membrane, whereas FAT/CD36(a fatty acid transporter) was relocated in plasma membrane.
Our investigations concerning metabolic modulators revealed that the pretreatment myocytes with a CPT-1 inhibitor(perhexiline), which is an inhibitor of mitochondrial fatty acid uptake, partially restored palmitate-induced insulin-resistance. Furthermore, perhexiline protected myocytes from palmitate-induced mitochondrial dysfunction. From these results, the mitochondrial protection may be a key factor for the prevention against myocardial insulin resistance.

Research Products

• [Journal Article] Effects of nitric oxide on mitochondrial permeability transition pore and thiol-mediated responses in cardiac myocytes (2012)
  • Author(s): Ohtani H, Katoh H, Tanaka T, Saotome M, Urushida T, Satoh H, Hayashi H
  • Journal Title: Nitric Oxide Volume: 26(2) Pages: 95-101
  • Peer Reviewed
• [Journal Article] Intravenous glutathione prevents renal oxidative stress after coronary angiography more effectively than oral N-acetylcysteine (2011)
  • Author(s): Saitoh T, Satoh H, Nobuhara M, Machii M, Tanaka T, Ohtani H, Saotome M, Urushida T, Katoh H, Hayashi H
  • Journal Title: Heart Vessels Volume: 26(5) Pages: 465-72
  • Peer Reviewed
• [Journal Article] Extracellular acidosis suppresses endothelial function by inhibiting store-operated Ca^<2+> entry via non-selective cation channels (2009)
  • Author(s): Asai M, Takeuchi K, Saotome M, Urushida T, Katoh H, Satoh H, Hayashi H, Watanabe H
  • Journal Title: Cardiovasc. Res Volume: 83 Pages: 97-105
  • Peer Reviewed
• [Journal Article] Protein phosphatase inhibitor-1 augments a protein kinase A-dependent increase in the Ca^<2+> loading of the sarcoplasmic reticulum without changing its Ca^<2+> release (2009)
  • Author(s): Kawashima H, Satoh H, Saotome M, Urushida T, Katoh H, Hayashi H
  • Journal Title: Circ. J. Volume: 73 Pages: 1133-1140
  • Peer Reviewed
• [Journal Article] Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia/reperfusion injury (2009)
  • Author(s): Saotome M, Katoh H, Yaguchi Y, Tanaka T, Urushida T, Satoh H, Hayashi H.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol Volume: 296 Pages: H1125-H1132
  • Peer Reviewed
• [Journal Article] Delayed enhancement on cardiac magnetic resonance and clinical, morphological and electrocardiographical features in hypertrophic cardiomyopathy (2009)
  • Author(s): Satoh H, Matoh F, Shiraki K, Saitoh T, Odagiri K, Saotome M, Usushida T, Katoh H, Takehara Y, Sakahara H, Hayashi H
  • Journal Title: J. Cardiac. Fail Volume: 15 Pages: 419-427
  • Peer Reviewed
• [Journal Article] Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes (2009)
  • Author(s): Odagiri K, Katoh H, Kawashima H, Tanaka T, Ohtani H, Saotome M, Urushida T, Satoh H, Hayashi H
  • Journal Title: J Mol Cell Cardiol Volume: 46(6) Pages: 989-97
  • Peer Reviewed
• [Presentation] A Novel ex vivo Cardiac Insulin Resistance Model Using Differentiated H9c2 Cell and Saturated Fatty Acids (2011)
  • Author(s): Nobuhara M, Saotome M, Watanabe T, Urushida T, Katoh H, Satoh H, Hayashi H
  • Organizer: 第28回国際心臓研究学会日本部会
  • Place of Presentation: 東京
  • Year and Date: 20111200
• [Presentation] Saturated fatty acid impairs glucose uptakes and accelerates FAT/CD36 retention at plasma membrane in differentiated H9c2 Cardiomyocytes (2011)
  • Author(s): Nobuhara M, Saotome M, Watanabe T, Urushida T, Katoh H, Satoh H, Hayashi H
  • Organizer: 日本循環器学会総会
  • Place of Presentation: 横浜
  • Year and Date: 20110800
• [Presentation] A novel ex vivo model to investigate metabolic deficiency in cardiac myocytes-differentiated H9c2 cells to assess the insulin-resistant heart (2011)
  • Author(s): Nobuhara M, Saotome M, Watanabe T, Urushida T, Katoh H, Satoh H, Hayashi H
  • Organizer: 55^<th> annual Biophysical Meeting
  • Place of Presentation: Baltimore, USA
  • Year and Date: 20110300
• [Presentation] Protein phosphatase inhibitor-1 can augment a protein kinase A-dependent increase in the SR Ca^<2+> loading without changing the SR Ca^<2+> release (2010)
  • Author(s): Satoh H, Kawashima H, Saotome M, Katoh H, Hayashi H
  • Organizer: XX World Congress of the International Society for Heart Research
  • Place of Presentation: Kyoto
  • Year and Date: 20100500
• [Presentation] Transient mitochondrial permeability transition pore(mPTP) opening by hydrogen peroxide affords cardiac protection from reperfusion injury (2010)
  • Author(s): Saotome M, Katoh H, Tanaka T, Nobuhara M, Saito T, Urushida T, Satoh H, Hayashi H
  • Organizer: 20^<th> world congress of ISHR
  • Place of Presentation: Kyoto
  • Year and Date: 20100500
• [Presentation] Protein Phosphatase Inhibitor-1 can Augment a Protein Kinase A-dependent Increase in the SR Ca^<2+> Loading Without Changing the SR Ca^<2+> Release (2009)
  • Author(s): Satoh H, Kawashima H, Saotome M, Urushida T, Katoh H, Hayashi H
  • Organizer: The 26^<th> Annual Meeting of the ISHR
  • Place of Presentation: Sapporo
  • Year and Date: 20091200
• [Presentation] Reactive Oxygen Species(ROS) control mitochondrial motility (2009)
  • Author(s): Saotome M, Hayashi H, Hajnoczky G
  • Organizer: ESC congress
  • Place of Presentation: Barcelona
  • Year and Date: 20090800
• [Presentation] Delayed Enhancement on Cardiac Magnetic Resonance and Clinical, Morphological and ECG Features in Hypertrophic Cardiomyopathy (2009)
  • Author(s): Satoh H, Matoh F, Shiraki K, Saitoh T, Odagiri K, Saotome M, Urushida T, Katoh H, Hayashi H
  • Organizer: 17^<th> Asian Pacific Congress of Cardiology
  • Place of Presentation: Kyoto
  • Year and Date: 20090500
• [Patent(Industrial Property Rights)] 心不全の心筋インスリン抵抗性を再現したex vivo心筋細胞、その作製方法および該心筋細胞を用いたスクリーニング方法 (2011)
  • Inventor(s): 早乙女雅夫、林秀晴
  • Industrial Property Rights Holder: 浜松医科大学
  • Industrial Property Number: 特許、特願2011-155940
  • Filing Date: 2011-07-14