Roles of PKC Isoforms in Development of Diabetes-Induced Cardiovascular Complications

  • Isil Ozakca
  • A. Tanju Ozcelikay
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 9)


Diabetes-induced cardiovascular abnormalities are the major causes of mortality and morbidity in diabetic populations. Vascular complications of diabetes can be evaluated as microvascular anomalies leading to retinopathy, nephropathy, and neuropathy, and macrovascular anomalies causing atherosclerosis, coronary artery disease, and peripheral vascular disease. Independent of coronary artery disease and hypertension, cardiomyopathy is also an important abnormality that can occur in the diabetic heart. Hyperglycemia, hyperinsulinemia related to insulin resistance, and increased levels of free fatty acids and lipids seem to have prominent roles in the development of microvascular and macrovascular complications and diabetic cardiomyopathy. Several mechanisms can be implicated in these complications, including increased polyol pathway flux, enhanced nonenzymatic glycation, and intracellular formation of advanced glycation end products (AGEs), activation of protein kinase C (PKC) isoforms, and increased hexosamine pathway activity. The focus of this chapter is recent concepts regarding PKC isoform-specific activation mechanisms and actions that have implications for the development of PKC-targeted therapeutics in diabetic complications. The PKC family of serine/threonine kinases have been associated with a diverse array of biological responses in health and disease. In diabetes, activation of different isoforms of PKC is associated with many pathologies seen in the retina, kidneys, vasculature, and heart. Therefore, inhibition of PKC isoforms can be evaluated as a therapeutic target for preventing of diabetic complications. In this regard, clinical trials using ruboxistaurin, a PKC-β isoform inhibitor, have promising results for treatment of diabetic retinopathy, nephropathy, and endothelial dysfunction.


PKC Diabetes Insulin resistance Diabetic complications PKC inhibitors 


  1. 1.
    Geraldes P, King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106:1319–1331PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
  3. 3.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  4. 4.
    Obrosova IG, Minchenko AG, Vasupuram R et al (2003) Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and vascular endothelial growth factor overexpression in streptozotocin-diabetic rats. Diabetes 52:864–871PubMedCrossRefGoogle Scholar
  5. 5.
    Wendt T, Harja E, Bucciarelli L et al (2006) Rage modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. Atherosclerosis 185:70–77PubMedCrossRefGoogle Scholar
  6. 6.
    Koya D, King GL (1998) Protein kinase C activation and the development of diabetic complications. Diabetes 47:859–866PubMedCrossRefGoogle Scholar
  7. 7.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRefGoogle Scholar
  8. 8.
    Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Inoue M, Kishimoto A, Takai Y et al (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem 252:7610–7616PubMedGoogle Scholar
  10. 10.
    Freeley M, Kelleher D, Long A (2011) Regulation of protein kinase C function by phosphorylation on conserved and non-conserved sites. Cell Signal 23:753–762PubMedCrossRefGoogle Scholar
  11. 11.
    Steinberg SF (2012) Cardiac actions of protein kinase C isoforms. Physiology (Bethesda) 27:130–139CrossRefGoogle Scholar
  12. 12.
    Steinberg SF (2008) Structural basis of protein kinase C isoform function. Physiol Rev 88:1341–1378PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Das Evcimen N, King GL (2007) The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res 55:498–510PubMedCrossRefGoogle Scholar
  14. 14.
    Newton AC (1995) Protein kinase C: structure, function and regulation. Minireview. J Biol Chem 270:28495–28498PubMedCrossRefGoogle Scholar
  15. 15.
    Pears C, Stabel S, Cazaubon S et al (1992) Studies on the phosphorylation of protein kinase C-α. Biochem J 283:515–518PubMedGoogle Scholar
  16. 16.
    Lynch JJ, Ferro TJ, Blumenstock FA et al (1990) Increased endothelial albumin permeability mediated by protein kinase C activation. J Clin Invest 85:1991–1998PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Wolf BA, Williamson JR, Easom RA et al (1991) Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels. J Clin Invest 87:31–38PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Xia P, Aiello LP, Ishii H et al (1996) Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018–2026PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Harhaj NS, Felinski EA, Wolpert EB et al (2006) VEGF activation of protein kinase C stimulates occludin phosphorylation and contributes to endothelial permeability. Invest Ophthalmol Vis Sci 47:5106–5115PubMedCrossRefGoogle Scholar
  20. 20.
    Hink U, Li H, Mollnau H et al (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:e14–e22PubMedCrossRefGoogle Scholar
  21. 21.
    Cardillo C, Campia U, Bryant MB et al (2002) Increased activity of endogenous endothelin in patients with type 2 diabetes mellitus. Circulation 106:1783–1787PubMedCrossRefGoogle Scholar
  22. 22.
    Cosentino F, Eto M, De Paolis P et al (2003) High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 107:1017–1023PubMedCrossRefGoogle Scholar
  23. 23.
    Inoguchi T, Li P, Umeda F et al (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945PubMedCrossRefGoogle Scholar
  24. 24.
    Inoguchi T, Battan R, Handler E et al (1992) Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA 89:11059–11063PubMedCrossRefGoogle Scholar
  25. 25.
    Shiba T, Inoguchi T, Sportsman JR et al (1993) Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Physiol 265:E783–E793PubMedGoogle Scholar
  26. 26.
    Babazono T, Kapor-Drezgic J, Dlugosz JA et al (1998) Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells. Diabetes 47:668–676PubMedCrossRefGoogle Scholar
  27. 27.
    Koya D, Jirousek MR, Lin YW et al (1997) Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 100:115–126PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375:2267–2277PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Idris I, Gray S, Donnelly R (2001) Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia 44:659–673PubMedCrossRefGoogle Scholar
  30. 30.
    Farese RV (2002) Function and dysfunction of aPKC isoforms for glucose transport in insulin-sensitive and insulin resistant states. Am J Physiol Endocrinol Metab 283:E1–E11PubMedGoogle Scholar
  31. 31.
    Farese RV, Sajan MP, Standaert ML (2005) Atypical protein kinase C in insulin action and insulin resistance. Biochem Soc Trans 33:350–353PubMedCrossRefGoogle Scholar
  32. 32.
    Davidoff AJ, Davidson MB, Carmody MW et al (2004) Diabetic cardiomyocyte dysfunction and myocyte insulin resistance: role of glucose-induced PKC activity. Mol Cell Biochem 262:155–163PubMedCrossRefGoogle Scholar
  33. 33.
    Bowman JC, Steinberg SF, Jiang TR et al (1997) Expression of protein kinase Cβ in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest 100:2189–2195PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Gu X, Bishop SP (1994) Increased protein-kinase-C and isozyme redistribution in pressure-overload cardiac-hypertrophy in the rat. Circ Res 75:926–931PubMedCrossRefGoogle Scholar
  35. 35.
    Bowling N, Walsh RA, Song GJ et al (1999) Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 99:384–391PubMedCrossRefGoogle Scholar
  36. 36.
    Alden KJ, Goldspink PH, Ruch SW et al (2002) Enhancement of L-type Ca2+ current from neonatal mouse ventricular myocytes by constitutively active PKC-β II. Am J Physiol Cell Physiol 282:C768–C774PubMedCrossRefGoogle Scholar
  37. 37.
    Huang L, Wolska BM, Montgomery DE et al (2001) Increased contractility and altered Ca2+ transients of mouse heart myocytes conditionally expressing PKCβ. Am J Physiol Cell Physiol 280:C1114–C1120PubMedGoogle Scholar
  38. 38.
    Wakasaki H, Koya D, Schoen FJ et al (1997) Targeted overexpression of protein kinase CβII isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci USA 94:9320–9325PubMedCrossRefGoogle Scholar
  39. 39.
    Hwang H, Robinson DA, Stevenson TK et al (2012) PKCβII modulation of myocyte contractile performance. J Mol Cell Cardiol 53:176–186PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Way KJ, Isshiki K, Suzuma K et al (2002) Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes 51:2709–2718PubMedCrossRefGoogle Scholar
  41. 41.
    Sharma K, Ziyadeh FN (1995) Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key modulator. Diabetes 44:1139–1146PubMedCrossRefGoogle Scholar
  42. 42.
    Chiu R, Boyle WJ, Meek J et al (1988) The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54:541–552PubMedCrossRefGoogle Scholar
  43. 43.
    Edwards AS, Faux MC, Scott JD et al (1999) Carboxyl-terminal phosphorylation regulates the function and subcellular localization of protein kinase C betaII. J Biol Chem 274:6461–6468PubMedCrossRefGoogle Scholar
  44. 44.
    Messina JL, Standaert ML, Ishizuka T et al (1992) Role of protein kinase C in insulin’s regulation of c-fos transcription. J Biol Chem 267:9223–9228PubMedGoogle Scholar
  45. 45.
    Franza BR Jr, Rauscher FJ 3rd, Josephs SF et al (1988) The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites. Science 239:1150–1153PubMedCrossRefGoogle Scholar
  46. 46.
    Zhang J, Wang L, Petrin J et al (1993) Characterization of site-specific mutants altered at protein kinase C beta 1 isosyme autophosphorylation sites. Proc Natl Acad Sci USA 90:6130–6134PubMedCrossRefGoogle Scholar
  47. 47.
    Ohshiro Y, Ma RC, Yasuda Y et al (2006) Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes 55:3112–3120PubMedCrossRefGoogle Scholar
  48. 48.
    Liu Y, Lei S, Gao X et al (2012) PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes. Clin Sci (Lond) 122:161–173CrossRefGoogle Scholar
  49. 49.
    Ikeda A, Matsushita S, Sakakibara Y (2012) Inhibition of protein kinase C β ameliorates impaired angiogenesis in type I diabetic mice complicating myocardial infarction. Circ J 76:943–949PubMedCrossRefGoogle Scholar
  50. 50.
    Rask-Madsen C, King GL (2005) Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. Arterioscler Thromb Vasc Biol 25:487–496PubMedCrossRefGoogle Scholar
  51. 51.
    Arikawa E, Ma RC, Isshiki K et al (2007) Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta’s actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes 56:1410–1420PubMedCrossRefGoogle Scholar
  52. 52.
    Connelly KA, Kelly DJ, Zhang Y et al (2009) Inhibition of protein kinase C in diabetic cardiomyopathy. Circ Heart Fail 2:129–137PubMedCrossRefGoogle Scholar
  53. 53.
    Inoguchi T, Xia P, Kunisaki M et al (1994) Insulin’s effect on protein kinase C and diacylglycerol induced by diabetes and glucose in vascular tissues. Am J Physiol 267:E369–E379PubMedGoogle Scholar
  54. 54.
    Mima A, Ohshiro Y, Kitada M et al (2011) Glomerular-specific protein kinase C-beta-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. Kidney Int 79:883–896PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96PubMedCrossRefGoogle Scholar
  56. 56.
    Rask-Madsen C, King GL (2007) Mechanisms of disease. Endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 3:46–56PubMedCrossRefGoogle Scholar
  57. 57.
    Ding Y, Vaziri ND, Coulson R et al (2000) Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am J Physiol Endocrinol Metab 279:E11–E17PubMedGoogle Scholar
  58. 58.
    Kearney MT, Duncan ER, Kahn M et al (2008) Insulin resistance and endothelial cell dysfunction: studies in mammalian models. Exp Physiol 93:158–163PubMedCrossRefGoogle Scholar
  59. 59.
    Rask-Madsen C, Li Q, Freund B et al (2010) Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab 11:379–389PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Naruse K, Rask-Madsen C, Takahara N et al (2006) Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes 55:691–698PubMedCrossRefGoogle Scholar
  61. 61.
    Ishii H, Jirousek MR, Koya D et al (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272:728–731PubMedCrossRefGoogle Scholar
  62. 62.
    Beckman JA, Goldfine AB, Gordon MB et al (2002) Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 90:107–111PubMedCrossRefGoogle Scholar
  63. 63.
    Mehta NN, Sheetz M, Price K et al (2009) Selective PKC beta inhibition with ruboxistaurin and endothelial function in type-2 diabetes mellitus. Cardiovasc Drugs Ther 23:17–24PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Tabit CE, Shenouda SM, Holbrook M et al (2013) Protein kinase C-β contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation 127:86–95PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Harja E, Chang JS, Lu Y et al (2009) Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis. FASEB J 23:1081–1091PubMedCrossRefGoogle Scholar
  66. 66.
    Koya D, Haneda M, Nakagawa H et al (2000) Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 14:439–447PubMedGoogle Scholar
  67. 67.
    Yokota T, Ma RC, Park JY et al (2003) Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes 52:838–845PubMedCrossRefGoogle Scholar
  68. 68.
    Rohde S, Sabri A, Kamasamudran R et al (2000) The alpha(1)-adrenoceptor subtype- and protein kinase C isoform-dependence of Norepinephrine’s actions in cardiomyocytes. J Mol Cell Cardiol 32:1193–1209PubMedCrossRefGoogle Scholar
  69. 69.
    Dixon BS, Sharma RV, Dickerson T et al (1994) Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle. Am J Physiol 266:C1406–C1420PubMedGoogle Scholar
  70. 70.
    Sugden PH (2003) An overview of endothelin signaling in the cardiac myocyte. J Mol Cell Cardiol 35:871–886PubMedCrossRefGoogle Scholar
  71. 71.
    Jalili T, Takeishi Y, Song G et al (1999) PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. Am J Physiol Heart Circ Physiol 277:H2298–H2304Google Scholar
  72. 72.
    Bayer AL, Heidkamp MC, Patel N et al (2003) Alterations in protein kinase C isoenzyme expression and autophosphorylation during progression of pressure overload-induced left ventricular hypertrophy. Mol Cell Biochem 242:145–152PubMedCrossRefGoogle Scholar
  73. 73.
    Simonis G, Briem SK, Schoen SP et al (2007) Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol Cell Biochem 305:103–111PubMedCrossRefGoogle Scholar
  74. 74.
    Braz JC, Gregory K, Pathak A et al (2004) PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med 10:248–254PubMedCrossRefGoogle Scholar
  75. 75.
    Kooij V, Boontje N, Zaremba R et al (2010) Protein kinase Cα and ξ phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium. Basic Res Cardiol 105:289–300PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Sumandea MP, Pyle WG, Kobayashi T et al (2003) Identification of a functionally critical protein kinase C phosphorylation residue of cardiac troponin T. J Biol Chem 278:35135–35144PubMedCrossRefGoogle Scholar
  77. 77.
    Malhotra R, D’Souza KM, Staron ML et al (2010) G q-mediated activation of GRK2 by mechanical stretch in cardiac myocytes: the role of protein kinase C. J Biol Chem 285:13748–13760PubMedCrossRefGoogle Scholar
  78. 78.
    Yang L, Liu G, Zakharov SI et al (2005) S1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. J Biol Chem 280:207–214PubMedGoogle Scholar
  79. 79.
    Auwerx JH, Chait A, Deeb SS (1989) Regulation of the low density lipoprotein receptor and hydroxymethylglutaryl coenzyme A reductase genes by protein kinase C and a putative negative regulatory protein. Proc Natl Acad Sci USA 86:1133–1137PubMedCrossRefGoogle Scholar
  80. 80.
    Kumar A, Chambers TC, Cloud-Heflin BA et al (1997) Phorbol ester-induced low density lipoprotein receptor gene expression in HepG2 cells involves protein kinase C-mediated p42/44 MAP kinase activation. J Lipid Res 38:2240–2248PubMedGoogle Scholar
  81. 81.
    Churchill E, Budas G, Vallentin A et al (2008) PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu Rev Pharmacol Toxicol 48:569–599PubMedCrossRefGoogle Scholar
  82. 82.
    Fleming I, Mohamed A, Galle J et al (2005) Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCα. Cardiovasc Res 65:897–906PubMedCrossRefGoogle Scholar
  83. 83.
    Cathcart MK, McNally AK, Morel DW et al (1989) Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein and conversion of low-density lipoprotein to a cytotoxin. J Immunol 142:1963–1969PubMedGoogle Scholar
  84. 84.
    Cathcart MK, Morel DW, Chisolm GM 3rd (1985) Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukoc Biol 38:341–350PubMedGoogle Scholar
  85. 85.
    Thallas-Bonke V, Thorpe SR, Coughlan MT et al (2008) Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha dependent pathway. Diabetes 57:460–469PubMedCrossRefGoogle Scholar
  86. 86.
    Menne J, Park JK, Boehne M et al (2004) Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes 53:2101–2109PubMedCrossRefGoogle Scholar
  87. 87.
    Wong SL, Lau CW, Wong WT et al (2011) Pivotal role of protein kinase Cdelta in angiotensin II-induced endothelial cyclooxygenase-2 expression: a link to vascular inflammation. Arterioscler Thromb Vasc Biol 31:1169–1176PubMedCrossRefGoogle Scholar
  88. 88.
    Bezy O, Tran TT, Pihlajamaki J et al (2011) PKCdelta regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J Clin Invest 121:2504–2517PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    He Z, Way KJ, Arikawa E et al (2005) Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium. J Biol Chem 280:15719–15726PubMedCrossRefGoogle Scholar
  90. 90.
    Churchill EN, Mochly-Rosen D (2007) The roles of PKCdelta and epsilon isoenzymes in the regulation of myocardial ischaemia/reperfusion injury. Biochem Soc Trans 35:1040–1042PubMedCrossRefGoogle Scholar
  91. 91.
    Geraldes P, Hiraoka-Yamamoto J, Matsumoto M et al (2009) Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15:1298–1306PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Kunisaki M, Bursell SE, Umeda F et al (1994) Normalization of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels. Diabetes 43:1372–1377PubMedCrossRefGoogle Scholar
  93. 93.
    Venugopal SK, Devaraj S, Yang T et al (2002) α-Tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-α. Diabetes 51:3049–3054PubMedCrossRefGoogle Scholar
  94. 94.
    Abdala-Valencia H, Cook-Mills JM (2006) VCAM-1 signals activate endothelial cell protein kinase Cα via oxidation. J Immunol 177:6379–6387PubMedCentralPubMedGoogle Scholar
  95. 95.
    Berdnikovs S, Abdala-Valencia H, McCary C et al (2009) Isoforms of vitamin E have opposing immunoregulatory funcitons during inflammation by regulating leukocyte recruitment. J Immunol 182:4395–4405PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Cook-Mills JM, Johnson JD, Deem TL et al (2004) Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. Biochem J 378:539–547PubMedCrossRefGoogle Scholar
  97. 97.
    McCary CA, Yoon Y, Panagabko C et al (2012) Vitamin E isoforms directly bind PKCα and differentially regulate activation of PKCα. Biochem J 441:189–198PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Tran K, Proulx PR, Chan AC (1994) Vitamin E suppresses DAG level in thrombin-stimulated endothelial cells through an increase of DAG kinase activity. Biochem Biophys Acta 1212:193–202PubMedCrossRefGoogle Scholar
  99. 99.
    Aiello LP, Clermont A, Arora V et al (2006) Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Invest Ophthalmol Visl Sci 47:86–92CrossRefGoogle Scholar
  100. 100.
    PKC-DRS Study Group (2005) The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C Beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54:2188–2197CrossRefGoogle Scholar
  101. 101.
    PKC-DMES Study Group (2007) Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch Ophthalmol 125:318–324CrossRefGoogle Scholar
  102. 102.
    Aiello LP, Davis MD, Girach A et al (2006) Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 113:2221–2230PubMedCrossRefGoogle Scholar
  103. 103.
    Aiello LP, Vignati L, Sheetz MJ et al (2011) Oral protein kinase C β inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2. Retina 31:2084–2094PubMedCrossRefGoogle Scholar
  104. 104.
    Tuttle KR, Bakris GL, Toto RD et al (2005) The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28:2686–2690PubMedCrossRefGoogle Scholar
  105. 105.
    Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, Bastyr EJ III (2005) Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther 27:1164–1180PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of PharmacologyAnkara UniversityAnkaraTurkey

Personalised recommendations