Study on cardiac hypertrophy and failure by lipid storage

• Project/Area Number: 20590859
• 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: Nagoya University
• Principal Investigator: OKUMURA Kenji Nagoya University, 大学院・医学系研究科, 寄附講座教授 (40262901)
• Co-Investigator(Kenkyū-buntansha): MURAKAMI Ryuichiro 名古屋大学, 医学部附属病院, 助教 (20418742) ; SEI Kenbu 名古屋大学, 大学院・医学系研究科, 寄附講座講師 (30378228)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脂質 / 心肥大 / 心不全 / カルニチン / JVSマウス / Lipids / マトリックスプロテアーゼ / Remodeling / Atherocsclerosis / Neovascularization / Cardiac hypertrophy / Heart Failure / アディポネクチン / 血管内皮機能

Research Abstract

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal re-absorption of carnitine due to mutations of the carnitine transporter OCTN2 gene, and is associated with hypertrophic cardiomyopathy. Heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors such as hypertension. We investigated the effects of surgically-induced pressure overload on the hearts of heterozygous mutants of a murine model of systemic carnitine deficiency, juvenile visceral steatosis mouse (jvs/+). At baseline, there were no differences in physical characteristics between WT and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in WT mice. Both WT and jvs/+ mice were subjected to ascending aortic constriction (AAC) with or without 1% L-carnitine supplementation. After AAC, (jvs/+)-AAC mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, reduced myocardial phosphocreatine-to-ATP ratio, and increased mortality compared with WT-AAC mice ; L-carnitine supplementation prevented these changes in (jvs/+)-AAC mice. Cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes of OCTN2 mutations and could be prevented by L-carnitine supplementation.

Research Products

• [Journal Article] Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers. (2010)
  • Author(s): Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T, Okumura K.
  • Journal Title: Metabolism. 59 Pages: 728-33
  • Peer Reviewed
• [Journal Article] Separating the mechanism-based and off-target actions of CETP inhibitors using CETP gene polymorphisms. (2010)
  • Author(s): Sofat R, Hingorani AD, Smeeth L, Humphries SE, Talmud PJ, Cooper J, Shah T, Sandhu MS, Ricketts SL, Boekholdt SM, Wareham N, Khaw KT, Kumari M, Kivimaki M, Marmot M, Asselbergs FW, van der Harst P, Dullaart RP, Navis G, van Veldhuisen DJ, Van Gilst WH, Thompson JF, McCaskie P, Palmer LJ, Arca M, Quagliarini F, Gaudio C, Cambien F, Nicaud V, Poirer O, Gudnason V, Isaacs A, Witteman JC, van Duijn CM, Pencina M, Vasan RS, D'Agostino RB Sr, Ordovas J, Li TY, Kakko S, Kauma H, Savolainen MJ, Kesaniemi YA,Sandhofer A, Paulweber B, Sorli JV, Goto A, Yokoyama S, Okumura K, Horne BD, Packard C, Freeman D, Ford I, Sattar N, McCormack V, Lawlor DA, Ebrahim S, Smith GD, Kastelein JJ, Deanfield J, Casas JP.
  • Journal Title: Circulation. 121 Pages: 52-62
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial nitric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells. (2010)
  • Author(s): Kataoka H, Murakami R, Numaguchi Y, Okumura K, Murohara T.
  • Journal Title: Eur J Pharmacol. 636 Pages: 36-41
  • Peer Reviewed
• [Journal Article] AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice. (2010)
  • Author(s): Sasaki T, Kuzuya M, Nakamura K, Cheng XW, Hayashi T, Song H, Hu L, Okumura K, Murohara T, Iguchi A, Sato K.
  • Journal Title: Atherosclerosis. 210 Pages: 430-437
  • Peer Reviewed
• [Journal Article] Endothelial function for the evaluation of anti-atherosclerotic drugs. (2010)
  • Author(s): Okumura K, Cheng XW.
  • Journal Title: Hypertens Res. 33 Pages: 780-781
  • NAID: 10027681423
• [Journal Article] Exercise training stimulates neovasculalization in response to ischemia via PI3K/Akt-dependent HIF-1. reactivation in advanced age. (2010)
  • Author(s): Cheng XW, Kuzuya M, Song H, Inoue A, Hu L, Kim W, Q D, Shi GP, Okumura K, Murohara T.
  • Journal Title: Circulation. 122 Pages: 707-716
  • Peer Reviewed
• [Journal Article] Ca2^+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats. (2010)
  • Author(s): Nishizawa T, Cheng XW, Jin Z, Obata K, Nagata K, Hirashiki A, Sasaki T, Noda A, Takeshita K, Izawa H, Shi GP, Kuzuya M, Okumura K, Murohara T.
  • Journal Title: J Hypertens. 28 Pages: 1515-1526
  • Peer Reviewed
• [Journal Article] High serum concentrations of pentosidine, an advanced glycation end product, are associated with low normal value of ankle-brachial index in apparently healthy men. (2010)
  • Author(s): Takahashi R, Imamura A, Yoshikane M, Suzuki M, Murakami R, Cheng XW, Numaguchi Y, Ikeda N, Murohara T, Okumura K.
  • Journal Title: Metabolism. in press
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial rutric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells. (2010)
  • Author(s): Kataoka H
  • Journal Title: Eur J Pharmacol. Volume: 636 Pages: 36-41
  • Peer Reviewed
• [Journal Article] ATl blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice. (2010)
  • Author(s): Sasaki T
  • Journal Title: Atherosclerosis Volume: 210 Pages: 430-437
  • Peer Reviewed
• [Journal Article] Renal protective effects and the prevention of contrast-induced nephropathy by atrial natriuretic peptide. (2009)
  • Author(s): Morikawa S, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Morita Y, Numaguchi Y, Okumura K, Murohara T.
  • Journal Title: J Am Coll Cardiol. 53 Pages: 1040-1046
  • Peer Reviewed
• [Journal Article] Mesenchymal stem cell-based gene therapy with prostacyclin synthase enhanced neovascularization in hindlimb ischemia. (2009)
  • Author(s): Ishii M, Numaguchi Y, Okumura K, Kubota R, Ma X, Murakami R, Naruse K, Murohara T.
  • Journal Title: Atherosclerosis. 206 Pages: 109-118
  • Peer Reviewed
• [Journal Article] Reply to "Renal protective effects and Prevention of contrast-induced nephropathy by atrial natriuretic peptide. Can it work?" (2009)
  • Author(s): Okumura K, Sone T, Morikawa S, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Morita Y, Numaguchi Y, Murohara T.
  • Journal Title: J Am Coll Cardiol. 54 Pages: 1193-1194
  • Peer Reviewed
• [Journal Article] Differentiation Capacity of Endothelial Progenitor Cells Correlates With Endothelial Function in Healthy Young Men. (2009)
  • Author(s): Miura M, Numaguchi Y, Ishii M, Kubota R, Takeuchi T, Imamura A, Murakami R, Kondo T, Okumura K, Murohara T.
  • Journal Title: Circ J. 73 Pages: 1324-1329
  • NAID: 10025932869
  • Peer Reviewed
• [Journal Article] Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats. (2009)
  • Author(s): Yamada T, Nagata K, Cheng XW, Obata K, Saka M, Miyachi M, Naruse K, Nishizawa T, Noda A, Izawa H, Kuzuya M, Okumura K, Murohara T, Yokota M.
  • Journal Title: Eur J Pharmacol. 615 Pages: 163-170
  • Peer Reviewed
• [Journal Article] Microsomal triglyceride transfer protein gene polymorphism strongly influences circulating malondialdehyde-modified low-density lipoprotein. (2009)
  • Author(s): Okumura K, Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T.
  • Journal Title: Metabolism. 58 Pages: 1306-1311
  • Peer Reviewed
• [Journal Article] Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers. (2009)
  • Author(s): Cheng XW, Okumura K, Kuzuya M, Jin Z, Nagata K, Obata K, Inoue A, Hirashiki A, Takeshita K, Unno K, Harada K, Shi GP, Yokota M, Murohara T.
  • Journal Title: J Cardiovasc Pharmacol. 54 Pages: 47-56
  • Peer Reviewed
• [Journal Article] Ablation of angiotensin IV receptor attenuates hypofibrinolysis via PAI-1 downregulation and reduces occlusive arterial thrombosis. (2009)
  • Author(s): Numaguchi Y, Ishii M, Kubota R, Morita Y, Yamamoto K, Matsushita T, Okumura K, Murohara T.
  • Journal Title: Arterioscler Thromb Vasc Biol. 29 Pages: 2102-2108
  • Peer Reviewed
• [Journal Article] Risk stratification of patients with prior myocardial infarction and advanced left ventricular dysfunction by gated myocardial perfusion SPECT imaging. (2009)
  • Author(s): Morishima I, Sone T, Tsuboi H, Mukawa H, Uesugi M, Morikawa S, Takagi K, Niwa T, Morita Y, Murakami R, Numaguchi Y, Murohara T, Okumura K.
  • Journal Title: J Nucl Cardiol. 15 Pages: 631-637
  • Peer Reviewed
• [Journal Article] Circulating malondialdehyde-modified low-densitylipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men. (2009)
  • Author(s): Takahashi R, Imamura A, Yoshikane M, Suzuki M, Cheng XW, Numaguchi Y, Ikeda N, Murohara T, Okumura K.
  • Journal Title: Clin Chim Acta. 399 Pages: 74-78
  • Peer Reviewed
• [Journal Article] Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers. (2009)
  • Author(s): Cheng XW, Okumura K, et al
  • Journal Title: J Cardiovasc Pharmacol. 54 Pages: 47-56
  • Peer Reviewed
• [Journal Article] Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats. (2009)
  • Author(s): Yamada T, Cheng XW, Okumura K, et al.
  • Journal Title: Fur J Pharmacol. 615 Pages: 163-170
  • Peer Reviewed
• [Journal Article] Mesenchymal stem cell-based gene therapy with prostacyclin synthaseenhanced neovascularization in hindlimb ischemia. (2009)
  • Author(s): Ishii M, Okumura K, Murakami R., et al.
  • Journal Title: Atherosclerosis. 206 Pages: 109-118
  • Peer Reviewed
• [Journal Article] Circulating malondialdehyde-modified low-density lipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men (2009)
  • Author(s): Takahashi R, Cheng XW, Okumura K, et al
  • Journal Title: Clin Chim Acta 399 Pages: 74-78
  • Peer Reviewed
• [Journal Article] Microsomal triglyceride transfer protein gene polymorphism strongly influences circulating malondialdehyde-modified low-density lipoprotein (2009)
  • Author(s): Okumura K, Murakami R, Cheng XW, et al.
  • Journal Title: Metabolism 58 Pages: 1306-1311
  • Peer Reviewed
• [Journal Article] The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects : the significance of plasma adiponectin levels. (2008)
  • Author(s): Imamura A, Takahashi R, Murakami R, Kataoka H, Cheng XW, Numaguchi Y, Murohara T, Okumura K.
  • Journal Title: Eur J Endocrinol. 158 Pages: 189-195
  • Peer Reviewed
• [Journal Article] Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment. (2008)
  • Author(s): Cheng XW, Murohara T, Kuzuya M, Izawa H, Sasaki T, Obata K, Nagata K, Nishizawa T, Kobayashi M, Yamada T, Kim W, Sato K, Shi GP, Okumura K, Yokota M.
  • Journal Title: Am J Pathol. 173 Pages: 358-369
  • Peer Reviewed
• [Journal Article] The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects : the significance of plasma adiponectin levels (2008)
  • Author(s): Imamura A, Cheng XW, Okumura K, et al.
  • Journal Title: Eur J Endocrinol 158 Pages: 189-195
  • Peer Reviewed
• [Presentation] Statin prevents apoptosis in response to oxidative stress and inflammation in atherogenic plaque via enhancement of antiapoptotic protein IAP-2 and Bcl-2 associated with activation of eNOs : implication for plaque stability. (2009)
  • Author(s): 成憲武、葛谷雅文、宋海珍、胡莉ナ、佐々木健、井上愛子、中村香江、奥村健二、室原豊明
  • Organizer: 第17回日本血管生物医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-12-03
• [Presentation] Superoxide-dependent cathepsin activation system is associated with hypertensive renal remodeling and represents a target for statin. (2009)
  • Author(s): Cheng XW, Okumura K, Sasaki T, Izawa H, Hirashiki Am Nagata K, Kuzuya M, Murohara T
  • Organizer: Scientific Sections.
  • Place of Presentation: Orlando, Florida, USA.
  • Year and Date: 2009-11-09
• [Presentation] Treatment of ApoE-deficient mice with statin inhibits the oxidative stress-dependent lysosomal protease cathepsin activation system : implication for plaque stability. (2008)
  • Author(s): Cheng XW, Kuzuya M, Okumura K, Nakamura K, Inoue A, Sasaki T, Song H, Takeshita K, Kim W, Shi GP, Murohara T
  • Organizer: Scientific Sections.
  • Place of Presentation: New Orleans, Louisiana, USA.
  • Year and Date: 2008-11-11
• [Presentation] Statin prevents apoptosis in response to oxidative stress in atherogenic plaque via enhancement of antiapoptotic protein IAP-2 : implication for plaque stability. (2008)
  • Author(s): Cheng XW, Okumura K, Hu L, Song H, Inoue A, Kuzuya M, Murohara T
  • Organizer: 5th China-Japan Cardiovascular Forum.
  • Place of Presentation: Beijing, China.
  • Year and Date: 2008-10-23
• [Presentation] Treatment of ApoE-deficient mice with statin inhibits theNADPH oxidase-dependent lysosomal protease cathepsin activation system : implication for plaque stability. (2008)
  • Author(s): Cheng XW, Okumura K, Kuzuya M, Inoue A, Song H, Hu L, Murohara T
  • Organizer: 4^<th>China-Japan Cardiovascular Forum.
  • Place of Presentation: Beijing, China.
  • Year and Date: 2008-10-19
• [Presentation] Very small low-density lipoprotein cholesterol level is a determinant of arterial stiffness in men with impaired glucose metabolism. (2008)
  • Author(s): Takahashi R, Okumura K, Yoshikane M, Ikeda N, Murohara T
  • Organizer: European Society of Cardiology, ESC Congress 2008
  • Place of Presentation: Munich
  • Year and Date: 2008-09-01
• [Remarks] ホームページ等