Diabetes Mellitus (DM) of type I (DM I) and type II (DM II) causes significant cardiovascular disease including diabetic cardiomyopathy (DC) and resulting in heart failure (HF) which presents a growing healthcare problem. Mechanisms which cause DC and DM related HF are only incompletely explored.
In Aim I we pursue novel findings showing that mitochondrial (Mito) proteins in diabetic (D) hearts exhibit excessive enzymatic O-linked glycosylation (O-GlcNAc), which is linked to diminished Mito complex function and a diminished ability to perform maximal cardiac work. Exposing cardiac myocytes (CM) to high glucose (HG) results in similar Mito changes. Viral vector based expression of the O-GlcNAcase enzyme (GCA) in CM of D hearts markedly improves Mito complex function and maximal cardiac function in spite of persistent DM. We also generated transgenic (Tg) mice with tetracycline (Tet) transactivator mediated conditional expression of (GCA) in CM. GCA expression in CM of D hearts results in decreased protein O-GlcNAc of Mito DNA encoded subunit I of complex IV.
In Aim II we pursue our novel findings that in CM exposed to high glucose (HG) markedly increased Mito fission and decreased Mito fusion occurs contributing to diminished Mito function. In CM of DM hearts increased Mito fission is also identified. In addition in DM hearts and in CM exposed to HG the fusion related protein OPA1 is decreased and excessively O- GlcNAcylated, whereas the Mito fission related proteins Fis1 and Drip1 are markedly increased. Preliminary results indicate that normalizing OPA1 levels and its O-GlcNAc status, using viral vector based expression of OPA1 or GCA transgenes (tge) in CM exposed to HG returns Mito fusion towards normal. Studies of Aim III are directed at increasing the activity of the pyruvate dehydrogenase complex (PDC) of the D heart and enhancing glucose oxidation (ox). Our results show, that inhibiting in the activity of PD kinase (PDK) 2 in the D heart using a viral vector expressed dominant negative PDK2 mutant, returns the decreased glucose ox to normal, markedly diminishes the excessive FA ox and improves the energetic efficiency of cardiac contraction. In an alternative approach to return D heart fuel flux to normal we will pursue our preliminary results that a shRNA directed at FA transporter 6 markedly diminishes its level in CM. These studies are conducted in DM I and DM II models. Novel insights and approaches to improve the function of the D heart in spite of the persistence of the D milieu may result.

Public Health Relevance

Diabetes mellitus is an increasingly important public health problem and leads to decreased function of the heart termed diabetic cardiomyopathy. Exposure to high glucose contributes to decreased cardiac function and the mechanisms which lead to these alterations are explored in this application. The identification of new targets to improve the function of the diabetic heart may result from this research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066917-12
Application #
8122111
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2000-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2011
Total Cost
$531,557
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Suarez, Jorge; Wang, Hong; Scott, Brian T et al. (2014) In vivo selective expression of thyroid hormone receptor ?1 in endothelial cells attenuates myocardial injury in experimental myocardial infarction in mice. Am J Physiol Regul Integr Comp Physiol 307:R340-6
Torres-Gonzalez, Moises; Gawlowski, Thomas; Kocalis, Heidi et al. (2014) Mitochondrial 8-oxoguanine glycosylase decreases mitochondrial fragmentation and improves mitochondrial function in H9C2 cells under oxidative stress conditions. Am J Physiol Cell Physiol 306:C221-9
Suarez, Jorge; McDonough, Patrick M; Scott, Brian T et al. (2013) Sorcin modulates mitochondrial Ca(2+) handling and reduces apoptosis in neonatal rat cardiac myocytes. Am J Physiol Cell Physiol 304:C248-56
Gawlowski, Thomas; Suarez, Jorge; Scott, Brian et al. (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-?-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287:30024-34
Fricovsky, Eduardo S; Suarez, Jorge; Ihm, Sang-Hyun et al. (2012) Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol 303:R689-99
Makino, Ayako; Suarez, Jorge; Gawlowski, Thomas et al. (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300:R1296-302
Makino, A; Scott, B T; Dillmann, W H (2010) Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53:1783-94
Hu, Yong; Suarez, Jorge; Fricovsky, Eduardo et al. (2009) Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J Biol Chem 284:547-55
Suarez, Jorge; Hu, Yong; Makino, Ayako et al. (2008) Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes. Am J Physiol Cell Physiol 295:C1561-8
Makino, Ayako; Platoshyn, Oleksandr; Suarez, Jorge et al. (2008) Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice. Am J Physiol Cell Physiol 295:C221-30

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