過去文獻指出PPARδ 對於心肌細胞的收縮功能與代謝調控是重要的。然而，對於PPARδ 在糖尿病引致的心肌病變及藥物產生強心作用上的角色仍不清楚。因此利用活體以及細胞試驗研究，高糖所引發的氧化壓力對於PPARδ 表現的影響。分別使用Wistar rats, 利用streptozotocin 所誘發的糖尿病大鼠、初生大鼠心肌細胞以及H9c2 心肌細胞株進行實驗。在糖尿病大鼠實驗中，心肌病變的產生伴隨顯著PPARδ 的表現下降。此外隨著高糖溶液抑制PPARδ 的表現後，心肌細胞內的氧化壓力、細胞大小以及蛋白質的合成都有明顯的增加。然而這些高糖溶液所引起的變化，都會被tiron 或PD98059 (MEK/ERK 阻斷劑)給破壞。進一步，我們使用digoxin，探討PPARδ 在藥物的強心作用中，扮演什麼角色。連續20天給予糖尿病大鼠digoxin(500 μg/kg/day, I.P)後，心肌PPARδ 的表現明顯的恢
復，且伴隨著心臟搏出量的提升。此外經過digoxin 治療後，脂質堆積在心臟的現象也消失了。被減弱的心肌旋轉蛋白I (troponin I) 磷酸化，在經過治療也有明顯回復的情形。同時，在初生大鼠心肌細胞與H9c2 細胞的實驗中也發現digoxin可以增加PPARδ 的表現。Digoxin 會增加細胞內的鈣離子濃度，而藉由BAPTA-AM, cyclosporine A, 或KN93 則會抑制原先Digoxin 促進PPARδ 表現的
作用。BAPTA-AM 也會抑制digoxin 刺激後，脂肪酸氧化作用基因表現量增強的現象。因此，鈣離子的路徑確實參與digoxin 促進PPARδ 與脂質氧化作用基因表現增加的作用。Dinitrophenol 是一個氧化磷酸化作用抑制劑，它抑制原先Digoxin促進心肌旋轉蛋白I 的磷酸化作用，但不會影響digoxin 對PPARδ 的作用。除此之外，siRNA-PPARδ 會抑制digoxin 對細胞所產生的作用，包含：增強心肌旋轉蛋白的磷酸化作用、提升PPARδ 以及脂肪酸氧化作用的基因表現量。進一步我們研究dobutamine 及 ginsenoside Rh2 產生強心作用時，其對於PPARδ 表現的調控情形，結果發現，這兩個藥物也可以透過鈣離子依賴性路徑來調控PPARδ 的表現。綜合上述結果發現，細胞在接受高糖刺激後，ROS 的生成與MEK/ERK的活化是造成PPARδ 表現量下降的原因。此外強心藥物的作用裡，例如digoxin
，可能是透過鈣離子驅動的訊息路徑，提升PPARδ 的表現量與心肌旋轉蛋白的磷酸化；而這兩個變化對於強心作用而言都是重要的。

Previous study indicated that cardiac PPARδ-dependent maintenance of inotropic function and metabolic effect is crucial for cardiomyocytes. However, the roles of PPARδ in the diabetic cardiomyopathy and cardiotonic agents are not clear. First, we investigated the effect of hyperglycemia-induced oxidative stress on the expression of cardiac PPARδ both in vivo and in vitro. We used male Wistar rats to examine the effect of hyperglycemia on the PPARδ expression in streptozotocin-induced diabetic rats, primary neonatal rat cardiomyocytes, and H9c2 embryonic rat cardiomyocytes. Cardiomyopathy induced in streptozotocin-diabetic rats was associated with a marked decrease in PPARδ expression. Also, ROS production, cell size, and protein synthesis were increased while PPARδ expression was reduced in cells exposed to hyperglycemia in vitro. However, these glucose-induced changes were abolished in
the presence of tiron or PD98059 (MEK/ERK inhibitor). Further, we employed digoxin to investigate the role of PPARδ in the cardiotonic action. After a 20-day digoxin treatment (500 μg/kg/day, I.P), the PPARδ expression was elevated in heart of digoxin-treated diabetic rats with a marked change in cardiac output. Also, the cardiac lipid accumulation was reduced in these digoxin-treated diabetic rats. Troponin I phosphorylations reduced in diabetic rats were reversed by digoxin. Otherwise, digoxin also caused an increase of PPARδ expression in neonatal cardiomyocytes or H9c2 cells. Intracellular Ca2+ concentration was raised in hyperglycemia-treated cells by digoxin. Moreover, the digoxin-induced increase of PPARδ expression in hyperglycemia-treated cells was blocked by pretreatment with BAPTA-AM, cyclosporine A, or KN93. The fatty acid oxidation gene expressions increased by digoxin were also blocked by BAPTA-AM. Thus, the Ca2+ signal is considered to
involve in the digoxin-increased PPARδ and fatty acid oxidative gene expressions. Oxidative phosphorylation inhibitor, dinitrophenol suppressed the digoxin-increased
troponin I phosphorylations but not the PPARδ expression. Moreover, siRNA-PPARδ inhibited these actions of digoxin including troponin phosphorylation, PPARδ and fatty acid oxidative gene expressions in cells. Furthermore, we investigated the effect of dobutamine and ginsenoside Rh2 on the PPARδ expression in the cardiotonic action. Results showed the effect of both cardiotonic agents on the PPARδ regulation via the Ca2+-dependent signal pathway. In conclusion, the obtained results suggest that inhibitors of ROS production or MEK/ERK activation are involved in reduction of cardiac PPARδ expression in response to hyperglycemia. In addition, the action of cardiotonic agents, such as digoxin, seems to be induced through Ca2+-trigger signals to enhance PPARδ expressions and troponin I phosphorylation that both are important in the cardiotonic action.

1. Kannel WB, Hjortland M, and Castelli WP. Role of diabetes in congestive heart failure: The Framingham Study. Am. J. Cardiol. 1976; 34: 29-34
2. Kannel WB, McGee DL. Diabetes and glucose intolerance as risk factors for cardiovascular disease: The Framingham Study. Diabetes Care 1979; 2:120-126
3. Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mellitus. Eur. Heart J. 1988; 9: 256-264
4. Herlitz J, Malmberg K, Karlsson B, Ryden L and Hjalmarson A. Mortality and morbidity during a five year follow up of diabetics with myocardial infarction. Acta Med. Scand. 1998; 24: 31-38
5. Hayat SA, Patel B, Khattar RS, Malik RA. Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin Sci (Lond). 2004;107:539-557
6. Fonarow GC, Srikanthan P. Diabetic cardiomyopathy. Endocrinol Metab Clin North Am 2006; 35: 575-599
7. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 2006; 98: 596-605
8. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006; 291: H1489–H1506
9. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007; 115: 3213-3223
10. Tahiliani AG, McNeill JH. Diabetes-induced abnormalities in the myocardium. Life Sci 1986; 38:959-974
11. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Cardiovasc Drugs Ther 1994; 8:65-73
12. Scognamiglio R, Casara D, Avogaro A. Myocardial dysfunction and adrenergic innervation in patients with Type 1 diabetes mellitus. Diabetes Nutr Metab 2000; 13:346-349
13. Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol 1983; 244:E528-E535
14. Pierce GN, Dhalla NS. Sarcolemmal Na+-K+-ATPase activity in diabetic rat heart. Am J Physiol 1983; 245:C241-247
15. Penpargkul S, Schaible T, Yipintsoi T, Scheuer J. The effect of diabetes on performance and metabolism of rat hearts. Circ Res 1980; 47:911-921
16. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol 1995; 27:169-179
17. Rodrigues B, Cam MC, McNeill JH. Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem 1998;180:53-57
18. Eckel J, Reinauer H. Insulin action on glucose transport in isolated cardiac myocytes: signalling pathways and diabetes-induced alterations. Biochem Soc Trans 1990;18:1125-1127
19. Liedtke AJ, DeMaison L, Eggleston AM, Cohen LM, Nellis SH. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res 1988; 62:535-542
20. Malhotra A, Sanghi V. Regulation of contractile proteins in diabetic heart. Cardiovasc Res 1997; 34:34-40
21. Takeda N, Nakamura I, Hatanaka T, Ohkubo T, Nagano M. Myocardial mechanical and myosin isoenzyme alterations in streptozotocin-diabetic rats. Jpn Heart J 1988; 29:455-463
22. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji T, Kohzuki H, Suga H, Taniguchi S, Takaki M. Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol 2002; 282:H138-148
23. Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, Dincer UD, Besch HR Jr. Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes 2003; 52:1825-1836
24. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 2003; 278:44230-44237
25. Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci USA 1997; 94:9320-9325
26. Singh R, Barden A, Mori T. Beilin L. Advanced glycation end products: a review. Diabetologia 2001; 44:129-146
27. Rosen P, Du X. Tschope D. Role of oxygen derived free radicals for vascular dysfunction in the diabetic heart: prevention by α-tocopherol? Mol. Cell Biochem 1998; 188: 103-111
28. Soriano FG, Pacher P, Mabley J, Liaudet L and Szabo C. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ. Res 2001; 89: 684-691
29. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycaemic control and heart failure among adult patients with diabetes. Circulation 2001; 103: 2668-2673
30. Avendano GF, Agarwal RK, Bashey RI, Lyons MM, Soni BJ, Jyothirmayi GN, Regan TJ. Effects of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes 1999; 48:1443-1447
31. Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. Impact of diabetes on cardiac structure and function: The Strong Heart Study. Circulation 2000; 101: 2271-2276
32. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, Brownlee M. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 2003; 112:1049-1057
33. Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC, Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res 2003; 92:785-792
34. Ramasamy R. Aldose reductase: a novel target for cardioprotective interventions. Curr Drug Targets 2003; 4:625-632
35. Guo M, Wu MH, Korompai F, Yuan SY. Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiol Genomics 2003; 12:139-146
36. Ravingerova′ T, Barancı′k M, Strniskova′ M. Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol Cell Biochem 2003; 247:127-138
37. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997; 9: 180-186
38. Sugden PH, Bogoyevitch MA. Intracellular signalling through protein kinases in the heart. Cardiovasc Res 1995; 30: 478-492
39. Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Review Curr Opin Genet Dev 1994; 4: 82-89
40. Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, Johnson GL, Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 1994; 266:1719-1723
41. Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science 1995; 269: 403-407
42. Lange-Carter CA, Pleiman CE, Gardner AM, Blumer KJ, Johnson GL. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 1993; 260: 315-319
43. Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall C, Cohen P. MAPKAP kinase-2: A novel protein kinase activated by mitogen-activated protein kinase. EMBO J 1992; 11: 3985-3994
44. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994; 78:1027-1037
45. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-Jun mediated by MAP kinases. Nature 1991; 353:670-674
46. Takeishi Y, Huang Q, Abe J, Glassman M, Che W, Lee JD, Kawakatsu H, Lawrence EG, Hoit BD, Berk BC, Walsh RA. Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: Comparison with acute mechanical stretch. J Mol Cell Cardiol 2001; 33: 1637-1648
47. Yamazaki T, Tobe K, Hoh E, Maemura K, Kaida T, Komuro I, Tamemoto H, Kadowaki T, Nagai R, Yazaki Y. Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. J Biol Chem 1993; 268: 12069-12076
48. Kudoh S, Komuro I, Hiroi Y, Zou Y, Harada K, Sugaya T, Takekoshi N, Murakami K, Kadowaki T, Yazaki Y. Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J Biol Chem 1998; 273: 24037-24043
49. Hayashida W, Kihara Y, Yasaka A, Inagaki K, Iwanaga Y, Sasayama S. Stage-specific differential activation of mitogen-activated protein kinases in hypertrophied and failing rat hearts. J Mol Cell Cardiol 2001; 33:733-744
50. Lazou A, Sugden PH, Clerk A. Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart. Biochem J 1998; 332: 459-465
51. Ng DC, Long CS, Bogoyevitch MA. A role for the extracellular signal-regulated kinase and p38 mitogen-activated protein kinases in interleukin-1 beta-stimulated delayed signal transducer and activator of transcription 3 activation, atrial natriuretic factor expression, and cardiac myocyte morphology. J Biol Chem 2001; 276: 29490-29498
52. Clerk A, Bogoyevitch MA, Anderson MB, Sugden PH. Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine, and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J Biol Chem 1994; 269: 32848-32857
53. Yue TL, Gu JL, Wang C, Reith AD, Lee JC, Mirabile RC, Kreutz R, Wang Y, Maleeff B, Parsons AA, Ohlstein EH. Extracellular signalregulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem 2000; 275: 37895-37901
54. Xiao L, Pimental DR, Amin JK, Singh K, Sawyer DB, Colucci WS. MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol 2001; 33:779-787
55. Clerk A, Michael A, Sugden PH. Stimulation of multiple mitogen-activated protein kinase sub-families by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. Biochem J. 1998; 333:581-589
56. Pellieux C, Sauthier T, Aubert JF, Brunner HR, Pedrazzini T. AngiotensinII-induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice. J Hypertens 2000; 18: 1307-1317
57. Behr TM, Nerurkar SS, Nelson AH, Coatney RW, Woods TN, Sulpizio A, Chandra S, Brooks DP, Kumar S, Lee JC, Ohlstein EH, Angermann CE, Adams JL, Sisko J, Sackner-Bernstein JD, Willette RN. Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction. Circulation 2001; 11: 1292-1298
58. Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci USA 2001; 9: 12283-12288
59. Finn SG, Dickens M, Fuller SJ. c-Jun N-terminal kinase/interacting protein 1 inhibits gene expression in response to hypertrophic agonists in neonatal rat ventricular myocytes. Biochem J 2001; 358: 489-495
60. Choukroun G, Hajjar R, Kyriakis JM, Bonventre JV, Rosenzweig A, Force T. Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy. J Clin Invest 1998; 102: 1311-1320
61. Flesch M, Margulies KB, Mochmann HC, Engel D, Sivasubramanian N, Mann DL. Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading. Circulation 2001; 104: 2273-2276
62. Fein FS, Kornstein LB, Strobeck JE, Capasso JM, Sonnenblick EH. Altered myocardial mechanics in diabetic rats. Circ Res. 1980; 47:922-933
63. Ohtsuki I, Morimoto S. Troponin: regulatory function and disorders. Biochem Biophys Res Commun. 2008; 369:62-73
64. Metzger JM, Westfall MV. Covalent and noncovalent modification of thin filament action. The essential role of troponin in cardiac muscle regulation. Circ Res 2004; 94:146-158
65. Layland J, Solaro RJ, Shah AM. Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovasc Res. 2005; 66:12-21
66. Yasuda S, Coutu P, Sadayappan S, Robbins J, Metzger JM. Cardiac transgenic and gene transfer strategies converge to support an important role for troponin I in regulating relaxation in cardiac myocytes. Circ Res. 2007;101:377-386
67. Bootman MD, Berridge MJ. The elemental principles of calcium signaling. 1995; Cell. 83:675-678
68. Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson EN. Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo. J Biol Chem. 2000; 275:4545-4548
69. Passier R, Zeng H, Frey N, Naya FJ, Nicol RL, McKinsey TA, Overbeek P, Richardson JA, Grant SR, Olson EN. CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000; 105:1395-1406
70. Schaeffer PJ, Wende AR, Magee CJ, Neilson JR, Leone TC, Chen F, Kelly DP. Calcineurin and calcium/calmodulin-dependent protein kinase activate distinct metabolic gene regulatory programs in cardiac muscle. J Biol Chem. 2004; 279:39593-39603
71. Solaro RJ, Powers FM, Gao L, Gwathmey JK. Control of myofilament activation in heart failure. Circulation 1993; 87:38-43
72. Miyata S, Minobe W, Bristow M.R, Leinwand L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 2000; 86:386-390
73. Margossian SS, Anderson PA, Chantler PD, Deziel M, Umeda PK, Patel H, Stafford WF, Norton P, Malhotra A, Yang F, Caulfield JB, Slayter HS. Calcium regulation in the human myocardium affected by dilated cardiomyopathy: a structural basis for impaired Ca2+-sensitivity. Mol Cell Biochem 1999; 194:301-313
74. Harding SE, Brown LA, Wynne DG, Davies CH, Poole-Wilson PA. Mechanisms of β-adrenoceptor desensitisation in the failing human heart. Cardiovasc Res 1994; 28:1451-1460
75. Pieske B, Beyermann B, Breu V, Löffler BM, Schlotthauer K, Maier LS, Schmidt-Schweda S, Just H, Hasenfuss G. Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium. Circulation 1999; 99:1802-1809
76. Asano K, Dutcher DL, Port JD, Minobe WA, Tremmel KD, Roden RL, Bohlmeyer TJ, Bush EW, Jenkin MJ, Abraham WT, Raynolds MV, Zisman LS, Perryman MB, Bristow MR. Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation 1997; 95:1193-1200
77. Takeishi Y, Bhagwat A, Ball NA, Kirkpatrick DL, Periasamy M, Walsh RA. Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure. Am J Physiol 1999; 276:H53–H62
78. Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N. Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol 1997; 29:265-272
79. Pervaiz MH, Dickinson MG, Yamani M. Is digoxin a drug of the past? Cleve Clin J Med. 2006; 73:821-824
80. Besch HR Jr, Watanabe AM. The positive inotropic effect of digitoxin: independence from sodium accumulation. J Pharmacol Exp Ther. 1978; 207:958-965
81. van Veldhuisen DJ, Man in't Veld AJ, Dunselman PH, Lok DJ, Dohmen HJ, Poortermans JC, Withagen AJ, Pasteuning WH, Brouwer J, Lie KI. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol 1993; 22:1564-1573
82. Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG-trial. Int J Cardiol 2008; 123:138-146
83. Capasso JM, Puntillo E, Halpryn B, Olivetti G, Li P, Anversa P. Amelioration of effects of hypertension and diabetes on myocardium by cardiac glycoside. Am J Physiol. 199; 262:H734-H742
84. Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res. 1975; 36:185-196
85. Nanas S, Gerovasili V, Dimopoulos S, Pierrakos C, Kourtidou S, Kaldara E, Sarafoglou S, Venetsanakos J, Roussos C, Nanas J, Anastasiou-Nana M. Inotropic agents improve the peripheral microcirculation of patients with end-stage chronic heart failure. J Card Fail. 2008; 14:400-406
86. Xiao RP, Lakatta EG. Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells. Circ Res. 1993; 73:286-300
87. Xiao RP, Spurgeon HA, O'Connor F, Lakatta EG. Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling. J Clin Invest. 1994; 94:2051-2059
88. Port JD, Bristow MR. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol. 2001; 33:887-905
89. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions, Biochem. Pharmacol. 1999; 58:1685-1693
90. Wang Z, Li M, Wu WK, Tan HM, Geng DF. Ginsenoside Rb1 preconditioning protects against myocardial infarction after regional ischemia and reperfusion by activation of phosphatidylinositol-3-kinase signal transduction. Cardiovasc Drugs Ther. 2008; 22:443-452
91. He F, Guo R, Wu SL, Sun M, Li M. Protective effects of ginsenoside Rb1 on human umbilical vein endothelial cells in vitro. J Cardiovasc Pharmacol. 2007; 50:314-320
92. Deng J, Lv XT, Wu Q, Huang XN. Ginsenoside Rg1 inhibits rat left ventricular hypertrophy induced by abdominal aorta coarctation: involvement of calcineurin and mitogen-activated protein kinase signalings. Eur J Pharmacol. 2009; 608:42-47
93. Hwang JT, Kim SH, Lee MS, Kim SH, Yang HJ, Kim MJ, Kim HS, Ha J, Kim MS, Kwon DY. Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. Biochem Biophys Res Commun. 2007; 364:1002-1008
94. Ham YM, Lim JH, Na HK, Choi JS, Park BD, Yim H, Lee SK. Ginsenoside-Rh2-induced mitochondrial depolarization and apoptosis are associated with reactive oxygen species- and Ca2+-mediated c-Jun NH2-terminal kinase 1 activation in HeLa cells. J Pharmacol Exp Ther. 2006; 319:1276-1285
95. Bae EA, Kim EJ, Park JS, Kim HS, Ryu JH, Kim DH. Ginsenosides Rg3 and Rh2 inhibit the activation of AP-1 and protein kinase A pathway in lipopolysaccharide/interferon-gamma-stimulated BV-2 microglial cells. Planta Med. 2006; 72:627-633
96. Yang Q, Li Y. Roles of PPARs on regulating myocardial energy and lipid homeostasis J Mol Med. 2007; 85:697-706
97. Wittels B, Spann JF Jr. Defective lipid metabolism in the failing heart. J Clin Invest 1968; 47:1787-1794
98. Massie BM, Schaefer S, Garcia J, McKirnan MD, Schwartz GG, Wisneski JA, Weiner MW, White FC. Myocardial high-energy phosphate and substrate metabolism in swine with moderate left ventricular hypertrophy. Circulation 1995; 91:1814-1823
99. Corr PB, Creer MH, Yamada KA, Saffitz JE, Sobel BE. Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 1989; 83:927-936
100. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 2000; 97:1784-1789
101. Regan TJ, Weisse AB. Diabetic cardiomyopathy. J Am Coll Cardiol 1992; 19:1165-1166
102. Zoneraich S, Mollura JL. Diabetes and the heart: state of the art in the 1990s. Can J Cardiol 1993; 9:293-299
103. Kenno KA, Severson DL. Lipolysis in isolated myocardial cells from diabetic rat hearts. Am J Physiol 1985; 249:H1024-H1030
104. Denton RM, Randle PJ. Measurement of flow of carbon atoms from glucose and glycogen glucose to glyceride glycerol and glycerol in rat heart and epididymal adipose tissue. Effects of insulin, adrenaline and alloxan-diabetes. Biochem J 1967; 104:423-434
105. Paulson DJ, Crass MF 3rd. Endogenous triacylglycerol metabolism in diabetic heart. Am J Physiol 1982; 242:H1084-H1094
106. Kiec-Wilk B, Dembinska-Kiec A, Olszanecka A, Bodzioch M, Kawecka-Jaszcz K. The selected pathophysiological aspects of PPARs activation. J Physiol Pharmacol. 2005; 56:149-162
107. Barish GD, Narkar VA, Evans RM. PPARdelta: a dagger in the heart of the metabolic syndrome. J Clin Invest. 2006; 116:590-597
108. Cheng L, Ding G, Qin Q, Huang Y, Lewis W, He N, Evans RM, Schneider MD, Brako FA, Xiao Y, Chen YE, Yang Q. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 2004; 10:1245-1250
109. Cheng L, Ding G, Qin Q, Xiao Y, Woods D, Chen YE, Yang Q. Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes. Biochem Biophys Res Commun 2004; 313:277-286
110. Planavila A, Rodriguez-Calvo R, Jove M, Michalik L, Wahli W, Laguna JC, Vazquez-Carrera M. Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res 2005; 65:832-841
111. Pesant M, Sueur S, Dutartre P, Tallandier M, Grimaldi PA, Rochette L, Connat JL. Peroxisome proliferator-activated receptor delta (PPARdelta) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis. Cardiovasc Res 2006; 69: 440-449
112. Finck BN, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation.2007; 115:2540-2548
113. Rimbaud S, Garnier A, Ventura-Clapier R. Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure Pharmacol Rep. 2009; 61:131-138
114. Yu BC, Chang CK, Ou HY, Cheng KC, Cheng JT. Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats. Cardiovasc Res. 2008; 80:78-87
115. ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008; 79:208-217
116. Sack MN, Kelly DP. The energy substrate switch during development of heart failure: gene regulatory mechanisms. Int J Mol Med. 2009; 1:17-24
117. Bugger H, Abel ED. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci. 2008;114:195-210
118. Mathur A, Hong Y, Kemp BK, Barrientos AA, Erusalimsky JD. Evaluation of fluorescent dyes for the detection of mitochondrial membrane potential changes in cultured cardiomyocytes. Cardiovasc Res 2000; 46:126-138
119. Kimes BW, Brandt BL. Properties of a clonal muscle cell line from rat heart. Exp. Cell Res. 1976; 98: 367-381
120. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 1996; 271:2746-2753
121. Planavila A, Sánchez RM, Merlos M, Laguna JC, Vázquez-Carrera M. Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells. Biochim Biophys Acta. 2005; 1736:120-127
122. Fiordaliso F, Bianchi R, Staszewsky L, Cuccovillo I, Doni M, Laragione T, Salio M, Savino C, Melucci S, Santangelo F, Scanziani E, Masson S, Ghezzi P, Latini R. Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats. J Mol Cell Cardiol 2004; 37:959-968
123. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 2001; 98:5306-5311
124. Muscat GE, Dressel U. Cardiovascular disease and PPARdelta: targeting the risk factors. Curr Opin Investig Drugs 2005; 6:887-894
125. Jucker BM, Doe CP, Schnackenberg CG, Olzinski AR, Maniscalco K, Williams C, Hu TC, Lenhard SC, Costell M, Bernard R, Sarov-Blat L, Steplewski K, Willette RN. PPARdelta activation normalizes cardiac substrate metabolism and reduces right ventricular hypertrophy in congestive heart failure. J Cardiovasc Pharmacol 2007; 50:25-34
126. Vadlamudi RV, Rodgers RL, McNeill JH. The effect of chronic alloxan- and streptozotocin-induced diabetes on isolated rat heart performance. Can J Physiol Pharmacol 1982; 60:902-911
127. Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem 2004; 261:187-191
128. Rodrigues B, Cam MC, Kong J, Goyal RK, McNeill JH. Strain differences in susceptibility to streptozotocin-induced diabetes: effects on hypertriglyceridemia and cardiomyopathy. Cardiovasc Res 1997; 34:199-205
129. Billimoria FR, Katyare SS, Patel SP. Insulin status differentially affects energy transduction in cardiac mitochondria from male and female rats. Diabetes Obes Metab 2006; 8:67-74
130. Rodgers RL. Depressor effect of diabetes in the spontaneously hypertensive rat: associated changes in heart performance.Can J Physiol Pharmacol 1986; 64:1177-1184
131. Litwin SE, Raya TE, Anderson PG, Daugherty S, Goldman S. Abnormal cardiac function in the streptozotocin-diabetic rat. Changes in active and passive properties of the left ventricle. J Clin Invest 1990; 86:481-488
132. Mihm MJ, Seifert JL, Coyle CM, Bauer JA. Diabetes related cardiomyopathy time dependent echocardiographic evaluation in an experimental rat model. Life Sci 2001; 69:527-542
133. Liao Y, Takashima S, Zhao H, Asano Y, Shintani Y, Minamino T, Kim J, Fujita M, Hori M, Kitakaze M. Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice. Cardiovasc Res 2006; 70:107-116
134. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001;108:1429-1437
135. Zhang SL, To C, Chen X, Filep JG, Tang SS, Ingelfinger JR, Carrière S, Chan JS. Effect of renin-angiotensin system blockade on the expression of the angiotensinogen gene and induction of hypertrophy in rat kidney proximal tubular cells. Exp Nephrol 2001; 9:109-117
136. Fan YP, Weiss RH. Exogenous attenuation of p21(Waf1/Cip1) decreases mesangial cell hypertrophy as a result of hyperglycemia and IGF-1. J Am Soc Nephrol 2004; 15:575-584
137. Jonas JC, Laybutt DR, Steil GM, Trivedi N, Pertusa JG, Van de Casteele M, Weir GC, Henquin JC. High glucose stimulates early response gene c-Myc expression in rat pancreatic beta cells. J Biol Chem 2001; 276:35375-35381
138. Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, Sgroi DC, Groff A, Ferran C, Bonner-Weir S, Sharma A, Weir GC. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. Diabetes 2002; 51:413-423
139. Babu GJ, Lalli MJ, Sussman MA, Sadoshima J, Periasamy M. Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy. J Mol Cell Cardiol 2000; 32: 1447-1457
140. Wang L, Gout I, Proud CG. Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. J Biol Chem 2001; 276:32670-32677
141. Ueyama T, Kawashima S, Sakoda T, Rikitake Y, Ishida T, Kawai M, Yamashita T, Ishido S, Hotta H, Yokoyama M. Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. J Mol Cell Cardiol 2000; 32: 947-960
142. Sugden PH, Clerk A. ‘Stress-responsive’ mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 1998; 24:345-352
143. Lou H, Kaur K, Sharma AK, Singal PK. Adriamycin-induced oxidative stress, activation of MAP kinases and apoptosis in isolated cardiomyocytes. Pathophysiology 2006; 13:103-109
144. Westermann D, Rutschow S, Van Linthout S, Linderer A, Bücker-Gärtner C, Sobirey M, Riad A, Pauschinger M, Schultheiss HP, Tschöpe C. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 2006; 49: 2507-2513
145. Tate CA, Hyek MF, Taffet GE. The role of calcium in the energetics of contracting skeletal muscle. Sports Med. 1991; 12:208-217
146. Fein FS, Strobeck JE, Malhotra A, Scheuer J, Sonnenblick EH. Reversibility of diabetic cardiomyopathy with insulin in rats. Circ Res. 1981; 49:1251-1261
147. Fein FS, Kornstein LB, Strobeck JE, Capasso JM, Sonnenblick EH. Altered myocardial mechanics in diabetic rats. Circ Res. 1980; 47:922-933
148. Schiaffino S, Serrano A. Calcineurin signaling and neural control of skeletal muscle fiber type and size. Trends Pharmacol Sci. 2002; 23:569-575
149. Hokanson JF, Mercier JG, Brooks GA. Cyclosporine A decreases rat skeletal muscle mitochondrial respiration in vitro. Am J Respir Crit Care Med. 1995; 151:1848-1851
150. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347:645-650
151. Liu X, Takeda N, Dhalla NS. Troponin I phosphorylation in heart homogenate from diabetic rat. Biochim Biophys Acta 1996; 1316:78-84
152. Messer AE, Jacques AM, Marston SB. Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. J Mol Cell Cardiol. 2007; 42:247-259
153. Li L, Desantiago J, Chu G, Kranias EG, Bers DM. Phosphorylation of phospholamban and troponin I in beta-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol. 2000; 278:H769-H779
154. Pi Y, Kemnitz KR, Zhang D, Kranias EG, Walker JW. Phosphorylation of troponin I controls cardiac twitch dynamics: evidence from phosphorylation site mutants expressed on a troponin I-null background in mice. Circ Res. 2002; 90:649-656
155. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS. A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev. 1998; 12:2499-2509
156. Parsons SA, Wilkins BJ, Bueno OF, Molkentin JD. Altered skeletal muscle phenotypes in calcineurin Aalpha and Abeta gene-targeted mice. Mol Cell Biol. 2003; 23:4331-4343
157. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991; 66:807-815
158. Zhou L, Yu X, Cabrera ME, Stanley WC. Role of cellular compartmentation in the metabolic response to stress: mechanistic insights from computational models. Ann N Y Acad Sci. 2006; 1080:120-139
159. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991; 66:807-815
160. Zhou L, Yu X, Cabrera ME, Stanley WC. Role of cellular compartmentation in the metabolic response to stress: mechanistic insights from computational models. Ann N Y Acad Sci. 2006; 1080:120-139
161. Swärd K, Josefsson M, Lydrup ML, Hellstrand P. Effects of metabolic inhibition on cytoplasmic calcium and contraction in smooth muscle of rat portal vein Acta Physiol Scand. 1993; 148:265-272
162. Hudman D, Rainbow RD, Lawrence CL, Standen NB. The origin of calcium overload in rat cardiac myocytes following metabolic inhibition with 2, 4-dinitrophenol. J Mol Cell Cardiol. 2002; 34:859-871
163. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004; 2:1532-1539
164. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002; 418:797-801
165. Miura S, Kawanaka K, Kai Y, Tamura M, Goto M, Shiuchi T, Minokoshi Y, Ezaki O. An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation. Endocrinology. 2007;148:3441-3448