Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion

被引：69
作者：
Edwards, Kristin S. [1 ,2 ,3 ]
Ashraf, Sadia [1 ,2 ,3 ]
Lomax, Tyler M. [1 ,2 ,3 ]
Wiseman, Jessica M. [1 ,2 ,3 ]
Hall, Michael E. [1 ,2 ,3 ,4 ]
Gava, Fabio N. [1 ,2 ]
Hall, John E. [1 ,2 ]
Hosler, Jonathan P. [5 ]
Harmancey, Romain [1 ,2 ,3 ]
机构：
[1] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, 2500 N State St, Jackson, MS 39216 USA
[2] Univ Mississippi, Med Ctr, Mississippi Ctr Obes Res, Jackson, MS 39216 USA
[3] Univ Mississippi, Med Ctr, Mississippi Ctr Heart Res, Jackson, MS 39216 USA
[4] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA
[5] Univ Mississippi, Med Ctr, Dept Cell & Mol Biol, Jackson, MS 39216 USA
来源：
BASIC RESEARCH IN CARDIOLOGY | 2018年 / 113卷 / 06期
基金：
美国国家卫生研究院;
关键词：
Type; 2; diabetes; Myocardial infarction; Uncoupling protein; Cardiac metabolism; Mitochondrial function; COMPLEX-I ACTIVITY; CARDIAC EFFICIENCY; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; ELECTRON-TRANSPORT; DIABETES-MELLITUS; ISCHEMIA; HEART; MITOCHONDRIA; METABOLISM;
D O I：
10.1007/s00395-018-0707-9
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20-49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague-Dawley rats with partial loss of UCP3 (ucp3(+/-)). Wild-type littermates (ucp3(+/+)) were used as controls. Isolated working hearts from ucp3(+/-) rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3(+/-) hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3(+/-) cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.
引用
收藏
页数：16
相关论文
共 67 条
[1]   Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice [J].
Aasum, E ;
Hafstad, AD ;
Severson, DL ;
Larsen, TS .
DIABETES, 2003, 52 (02) :434-441
[2]   Relationship between obesity, insulin resistance, and coronary heart disease risk [J].
Abbasi, F ;
Brown, BW ;
Lamendola, C ;
McLaughlin, T ;
Reaven, GM .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2002, 40 (05) :937-943
[3]   A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart [J].
Ackers-Johnson, Matthew ;
Li, Peter Yiqing ;
Holmes, Andrew P. ;
O'Brien, Sian-Marie ;
Pavlovic, Davor ;
Foo, Roger S. .
CIRCULATION RESEARCH, 2016, 119 (08) :909-+
[4]   Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release [J].
Aidakkak, Mohammed ;
Stowe, David F. ;
Chen, Qun ;
Lesnefsky, Edward J. ;
Camara, Amadou K. S. .
CARDIOVASCULAR RESEARCH, 2008, 77 (02) :406-415
[5]   AMPK and metabolic adaptation by the heart to pressure overload [J].
Allard, Michael F. ;
Parsons, Hannah L. ;
Saeedi, Ramesh ;
Wambolt, Richard B. ;
Brownsey, Roger .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2007, 292 (01) :H140-H148
[6]   Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart [J].
Bakrania, Bhavisha ;
Granger, Joey P. ;
Harmancey, Romain .
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, 2016, (115)
[7]   Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function [J].
Bassi, M. ;
Nakamura, N. B. ;
Furuya, W. I. ;
Colombari, D. S. A. ;
Menani, J. V. ;
do Carmo, J. M. ;
da Silva, A. A. ;
Hall, J. E. ;
Colombari, E. .
ACTA PHYSIOLOGICA, 2015, 213 (04) :893-901
[8]   Generation of Oxygen Deficiency in Cell Culture Using a Two-Enzyme System to Evaluate Agents Targeting Hypoxic Tumor Cells [J].
Baumann, Raymond P. ;
Penketh, Philip G. ;
Seow, Helen A. ;
Shyam, Krishnamurthy ;
Sartorelli, Alan C. .
RADIATION RESEARCH, 2008, 170 (05) :651-660
[9]   Constitutive UCP3 overexpression at physiological levels increases mouse skeletal muscle capacity for fatty acid transport and oxidation [J].
Bezaire, V ;
Spriet, LL ;
Campbell, S ;
Sabet, N ;
Gerrits, M ;
Bonen, A ;
Harper, ME .
FASEB JOURNAL, 2005, 19 (06) :977-+
[10]   World Heart Day 2002 - The international burden of cardiovascular disease: Responding to the emerging global epidemic [J].
Bonow, RO ;
Smaha, LA ;
Smith, SC ;
Mensah, GA ;
Lenfant, C .
CIRCULATION, 2002, 106 (13) :1602-1605
1234567