June 2012 Researcher of the Month - Karen O'Shea, PhD
Myocardial infarction is a major contributor to morbidity and mortality, especially in diabetic patients. The mechanisms underlying the increased susceptibility to cardiac injury in diabetic patients are not well understood. Our previous work has revealed a central role for the receptor for advanced glycation end-products (RAGE) in myocardial infarction, indicating that RAGE contributes to oxidative stress consequent to ischemia/reperfusion and influences mitochondrial dysfunction that accompanies injury to the heart. Ligands for RAGE are increased under diabetic conditions and after ischemia/reperfusion, leading to increased downstream signaling.
Our laboratory has discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin family and an effector of Rho GTPases. The overall goal of my research is to investigate RAGE/mDia1 signaling in cardiomyocytes in response to ischemia/reperfusion injury. My hypothesis is that cardiomyocyte-specific RAGE and mDia-1, both highly upregulated in the murine heart after ischemia/reperfusion, signal devastating metabolic consequences in the myocardium, which trigger mitochondrial dysfunction.
1. Abel ED, O'Shea KM, Ramasamy R. Insulin Resistance: Metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol. 2012. Submitted.
2. Son N, Ananthakrishnan R, Yu S, Khan RS, Jiang H, Li Q, O’Shea KM, Homma S, Goldberg IJ, Ramasamy R. Cardiomyocyte Aldose Reductase Causes Heart Failure and Impairs Recovery from Ischemia. PLoS One. 2012. In revision.
3. Khairallah RJ, Kim J, O'Shea KM, O'Connell KA, Brown BH, Galvao T, Daneault C, Des Rosiers C, Polster BM, Hoppel CL, Stanley WC. Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS One. 2012;7(3):e34402.
4. Hecker PA, Galvao TF, O'Shea KM, Brown BH, Henderson R Jr, Riggle H, Gupte SA, Stanley WC. High-sugar intake does not exacerbate metabolic abnormalities or cardiac dysfunction in genetic cardiomyopathy. Nutrition. 2012 May;28(5):520-6.
5. Galvao TF, Brown BH, Hecker PA, O'Connell KA, O'Shea KM, Sabbah HN, Rastogi S, Daneault C, Des Rosiers C, Stanley WC. High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects. Cardiovasc Res. 2012 Jan 1;93(1):24-32.
6. Papanicolaou KN, Khairallah RJ, Ngoh G, Chikando A, Luptak I, O’Shea KM, Riley DD, Lugus JJ, Colucci WS, Lederer WJ, Stanley WC, and Walsh K. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 2011 31:1309-28.
7. Hecker PA, O’Shea KM, Galvao TF, Brown BH, and Stanley WC. Role of adiponectin in the development of high-fat diet-induced metabolic abnormalities in mice. Horm Metab Res 2011 43:100-5.
8. O’Shea KM, Chess DJ, Khairallah RJ, Hecker P, Lei B, Walsh K, Des Rosiers C, and Stanley WC. ω-3 polyunsaturated fatty acids prevent pressure overload-induced ventricular dilation and decrease in mitochondrial enzymes despite no change in adiponectin. Lipids Health Dis 2010 9:95.
9. Khairallah RJ, O’Shea KM, Brown BH, Khanna N, Des Rosiers C, and Stanley WC. Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+-induced mitochondrial permeability transition in normal and hypertrophied myocardium. J Pharmacol Exp Ther 2010 335:155-162.
10. Khairallah RJ, Sparagna GC, Khanna N, O’Shea KM, Hecker PA, Des Rosiers C, Fiskum G, and Stanley WC. Dietary supplementation with docosahexaenoic acid, but not eicosapentanoic acid, profoundly remodels cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim Biophys Acta 2010 1797:1555-1562.
11. O’Shea KM, Chess DJ, Khairallah RJ, Rastogi S, Hecker PA, Sabbah HN, Walsh K, and Stanley WC. Adiponectin plays a permissive role for structural and metabolic remodeling in mice subjected to pressure overload. Am J Physiol Heart Circ Physiol 2010 298:H1639-45.
12. Chess DJ, Khairallah RJ, O’Shea KM, Xu W, and Stanley WC. Dietary fat-induced adiposity elevates leptin, prevents down regulation of mitochondrial oxidative enzymes, and does not worsen cardiac dysfunction in response to pressure overload. Am J Physiol Heart Circ Physiol 2009 297:H1585-93.
13. O’Shea KM, Khairallah RJ, Sparagna GC, Xu W, Hecker PA, Robillard-Frayne I, Des Rosiers C, Kristian T, Murphy RC, Fiskum G, and Stanley WC. Dietary ω-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+-induced permeability transition. J Mol Cell Cardiol 2009 47:819-27.
14. Shah KB, Duda MK, O’Shea KM, Sparagna GC, Chess DJ, Khairallah RJ, Frayne-Robillard I, Xu W, Murphy RC, Des Rosiers C, and Stanley WC. High fat intake alters cardiac phospholipid composition and prevents cardioprotection with fish oil during pressure overload. Hypertension 2009 54:605-11.
15. Duda MK, O’Shea KM, and Stanley WC. Omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res 2009 84:33-41.
16. Duda MK, O'Shea KM, Tintinu A, Xu W, Khairallah RJ, Barrows BR, Chess DJ, Azimzadeh AM, Harris WS, Sharov VG, Sabbah HN, and Stanley WC. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res 2009 81:319-27.
17. Chess DJ, Xu W, Khairallah R, O'Shea KM, Kop WJ, Azimzadeh AM, and Stanley WC. The antioxidant tempol attenuates pressure overload-induced cardiac hypertrophy and contractile dysfunction in mice fed a high-fructose diet. Am J Physiol Heart Circ Physiol 2008 295:H2223-30.
18. Lei B, Chess DJ, Keung W, O'Shea KM, Lopaschuk GD, and Stanley WC. Transient activation of p38 MAP kinase and up-regulation of Pim-1 kinase in cardiac hypertrophy despite no activation of AMPK. J Mol Cell Cardiol 2008 45:404-10.
19. Duda MK, O’Shea KM, Lei B, Barrows BR, Azimzadeh A, McElfresh TE, Hoit BD, Kop WJ, and Stanley WC. Low carbohydrate/high fat diet attenuates pressure overload induced ventricular remodeling and dysfunction. J Card Fail 2008; 14:327-35.
20. Duda MK, O'Shea KM, Barrows BR, Lei B, Azimzadeh A, McElfresh TE, Hoit BD, and Stanley WC. Dietary supplementation with ω-3 polyunsaturated fatty acids increases plasma adiponectin and prevents ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res 2007;76:303-310.
21. King KL, Young ME, Kerner J, Huang H, O’Shea KM, Alexson SEH, Hoppel CL, and Stanley WC. Diabetes and activation of peroxisome proliferator activated receptor a selectively up-regulate mitochondrial thioesterase I activity and protein expression in the heart. J Lipid Res 2007;48:1511-1517.
22. Sharma N, Okere IC, Duda MK, Chess DJ, O'Shea KM, and Stanley WC. Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy. Cardiovasc Res 2007;73:257-268.
1. O’Shea KM, Chess DJ, Khairallah RJ, Walsh K, and Stanley WC. Pressure overload leads to severe concentric hypertrophy in adiponectin-deficient mice. J Card Fail 2009.
2. O’Shea KM, Chess DJ, Khairallah RJ, Walsh K, and Stanley WC. Pressure overload leads to severe concentric hypertrophy in adiponectin-deficient mice. Cardiovasc Drugs Ther 2009.
3. O’Shea KM, Chess DJ, Khairallah RJ, Walsh K, and Stanley WC. Severe concentric hypertrophy in response to pressure overload in mice lacking adiponectin. J Mol Cell Cardiol 2009.
4. O’Shea KM, Duda MK, Tintinu A, Xu W, Barrows BR, Khairallah RJ, Azimzadeh A, and Stanley WC. Eicosapentaenoic and docosahexaenoic acids (EPA+DHA), but not a-linolenic acid (ALA), elevate adiponectin, decrease inflammation, and prevent ventricular dysfunction with pressure overload-induced hypertrophy. Cardiovasc Drugs Ther 2008.
5. O'Shea KM, Duda M, McElfresh TA, Hoit BD, and Stanley WC. Fish oil prevents left ventricular remodeling and contractile dysfunction in pressure overload induced hypertrophy. FASEB J 2007.
6. O'Shea KM, Duda M, McElfresh TA, Hoit BD, and Stanley WC. A high fat diet decreases plasma insulin and prevents pressure overload induced cardiac dysfunction and hypertrophy. J Mol Cell Cardiol 2007.
7. O’Shea KM, Bray MS, Duda MK, Young ME, Harris W, and Stanley WC. Prevention of left ventricular remodeling and dysfunction in pressure overload by omega-3 fatty acid supplementation is associated with alterations in the cardiac lipidome, not changes in gene transcription. Circulation 2009.
I would like to stay in the field of academic research because it provides an environment to be creative and ask questions. In addition, I can work with students and teach them how to be problem-solvers. I enjoy explaining the basics of science, specifically biochemistry and physiology, in a way that others can understand to impart a strong foundation in science. I am passionate about doing research that leads to improvements in preventative care and it is important to perform novel mechanistic studies with clinical relevance. My long-term goal is to become an independent investigator in the cardiovascular disease field.