Abstract

Stimulating carbohydrate oxidation via pyruvate dehydrogenase (PDH) activation is known to irmprove contractile recovery of postischemic myocardium. We have determined that the benefits of activating PDH rely neither on glycolytic nor mitochondrial energy production. Instead, PDH-dependent changes in cytosolic redox state influence the recovery of the postischemic heart. Our results on PDH activation during the first hour of reperfusion in the in vivo heart of conscious pigs demonstrate reversal of early reperfusion injury that results in sustained improvement in contractility. Exciting new data show that stimulating pyruvate oxidation in reoxygenated cardiomyocytes improves contractile response to calcium, eliminates calcium overload, and improves contractile relaxation rate. Therefore, this study explores the hypothesis that PDH activation eliminates early reperfusion injury via favorable shifts in cytosolic redox balance that improve calcium homeostasis and mitochondrial function due to elimination of calcium overload and potentially, the integrity of the myofilaments. This hypothesis will be tested in both the single adult rat cardiomyocyte and in the isolated, perfused rat heart using a novel combination of techniques that include optical microscopy and 13C NMR spectroscopy.
Specific aims are: 1) Determine the effects of cytosolic redox state on intracellular calcium levels and contractile response to calcium in reoxygenated cardiomyocytes; 2) a) Evaluate the response of SERCA2a activity to augmented carbohydrate oxidation as a mechanism of improved calcium handling in reperfused hearts; b) if SERCA2a activity is improved by PDH activation in reperfused hearts then determine whether SERCA2a over expression in vivo rat hearts produces similar benefits to contractile recovery; 3) Determine the relationship between calcium and induced shifts in cytosolic redox state in affecting contractile function during augmented carbohydrate oxidation in reperfused myocardium; 4) Elucidate the relationship/competition between the calcium activated mitochondrial dehydrogenase, alpha-ketoglutarate dehydrogenase, versus activity of cytosolic reducing equivalent transport (malate-aspartate shuttle) in response to calcium load in the reperfused myocardium; 5) Examine the potential for augmented carbohydrate oxidation to reverse stunning via reduced myofilament protein degradation and improved calcium sensitivity. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056178-09
Application #
7056706
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Adhikari, Bishow B
Project Start
1996-12-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2010-04-30
Support Year
9
Fiscal Year
2006
Total Cost
$379,669
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Gropler, Robert J; Beanlands, Rob S B; Dilsizian, Vasken et al. (2010) Imaging myocardial metabolic remodeling. J Nucl Med 51 Suppl 1:88S-101S
O'Donnell, J Michael; Pound, Kayla; Xu, Xianyao et al. (2009) SERCA1 expression enhances the metabolic efficiency of improved contractility in post-ischemic heart. J Mol Cell Cardiol 47:614-21
O'Donnell, J Michael; Lewandowski, E Douglas (2005) Efficient, cardiac-specific adenoviral gene transfer in rat heart by isolated retrograde perfusion in vivo. Gene Ther 12:958-64
O'Donnell, J Michael; Kudej, Raymond K; LaNoue, Kathyrn F et al. (2004) Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. Am J Physiol Heart Circ Physiol 286:H2237-42
Kudej, Raymond K; White, Lawrence T; Kudej, Amelia B et al. (2002) Brief increase in carbohydrate oxidation after reperfusion reverses myocardial stunning in conscious pigs. Circulation 106:2836-41
Lewandowski, E Douglas (2002) Cardiac carbon 13 magnetic resonance spectroscopy: on the horizon or over the rainbow? J Nucl Cardiol 9:419-28
Lewandowski, E Douglas; Kudej, Raymond K; White, Lawrence T et al. (2002) Mitochondrial preference for short chain fatty acid oxidation during coronary artery constriction. Circulation 105:367-72
Griffin, J L; O'Donnell, J M; White, L T et al. (2000) Postnatal expression and activity of the mitochondrial 2-oxoglutarate-malate carrier in intact hearts. Am J Physiol Cell Physiol 279:C1704-9
O'Donnell, J M; White, L T; Lewandowski, E D (1999) Mitochondrial transporter responsiveness and metabolic flux homeostasis in postischemic hearts. Am J Physiol 277:H866-73
O'Donnell, J M; Doumen, C; LaNoue, K F et al. (1998) Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts. Am J Physiol 274:H467-76

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