Abnormal insulin signaling: Early detection of silent coronary artery disease-erectile dysfunction?

Current Pharmaceutical Design

Volumn 14, Issue 35, 2008, Pages 3737-3748

  Potenza, Maria Assunta ^a   Montagnani, Monica ^a  

^a UNIVERSITY OF BARI   (Italy)

Author keywords

Coronary artery disease; Endothelial dysfunction; Erectile dysfunction; Insulin resistance; Insulin signaling pathways

Indexed keywords

ANGIOTENSIN II; BIOLOGICAL MARKER; ENDOTHELIAL DERIVED HYPERPOLARIZING FACTOR; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN 1; FATTY ACID; GLITAZONE DERIVATIVE; GLUCOSE; HEAT SHOCK PROTEIN 90; INSULIN; INSULIN RECEPTOR KINASE; INSULIN RECEPTOR SUBSTRATE 1; INSULIN RECEPTOR SUBSTRATE 2; INTERCELLULAR ADHESION MOLECULE 1; METFORMIN; NITRIC OXIDE; NITRITE REDUCTASE [NAD(P)H]; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOPROTEIN PHOSPHATASE; PROSTAGLANDIN SYNTHASE; PROTEIN KINASE B; REACTIVE OXYGEN METABOLITE; SUPEROXIDE DISMUTASE; THROMBOXANE A2; UNCLASSIFIED DRUG; VASCULAR CELL ADHESION MOLECULE 1;

APOPTOSIS; CALCIUM TRANSPORT; CARDIOVASCULAR FUNCTION; CELL ADHESION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DIABETES MELLITUS; DIET THERAPY; DRUG MECHANISM; EARLY DIAGNOSIS; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; ERECTILE DYSFUNCTION; ESSENTIAL HYPERTENSION; EXERCISE; GLUCOSE HOMEOSTASIS; GLUCOSE TOLERANCE; HEART DEVELOPMENT; HEART FUNCTION; HEART MUSCLE CONTRACTILITY; HEART MUSCLE METABOLISM; HEMODYNAMICS; HOMEOSTASIS; HUMAN; HYPERTENSION; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIFESTYLE MODIFICATION; MUSCLE BLOOD FLOW; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN PROCESSING; PROTEIN SYNTHESIS; REVIEW; SEXUAL FUNCTION; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; VASCULARIZATION; VASODILATATION; WEIGHT REDUCTION; MALE; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; VASCULAR ENDOTHELIUM;

CORONARY ARTERY DISEASE; ENDOTHELIUM, VASCULAR; ERECTILE DYSFUNCTION; HUMANS; INSULIN; INSULIN RESISTANCE; MALE; SIGNAL TRANSDUCTION;

EID: 61449230001     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161208786898707     Document Type: Review

References (167)

1. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323: 27-36.
2. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 2007-18.
3. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-6.
4. Griffith OW, Stuehr DJ. Nitric oxide synthases: Properties and catalytic mechanism. Annu Rev Physiol 1995; 57: 707-36.
5. Govers R, Rabelink TJ. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 2001; 280: F193-206.
6. Fleming I, Bauersachs J, Busse R. Calcium-dependent and calcium-independent activation of the endothelial NO synthase. J Vasc Res 1997; 34: 165-74.
7. Garcia-Cardena G, Fan R, Stern DF, Liu J, Sessa WC. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 1996; 271: 27237-40.
8. Michell BJ, Chen Z, Tiganis T, Stapleton D, Katsis F, Power DA, et al. Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 2001; 276: 17625-8.
9. Michel JB, Michel T. The role of palmitoyl-protein thioesterase in the palmitoylation of endothelial nitric oxide synthase. FEBS Lett 1997; 405: 356-62.
10. Garcia-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998; 392: 821-4.
11. Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+- calmodulin and caveolin. J Biol Chem 1997; 272: 15583-6.
12. Gratton JP, Bernatchez P, Sessa WC. Caveolae and caveolins in the cardiovascular system. Circ Res 2004; 94: 1408-17.
13. Boo YC, Sorescu G, Boyd N, Shiojima I, Walsh K, Du J, et al. Shear stress stimulates phosphorylation of eNOS at Ser1179 by Akt- independent mechanisms - Role of Protein Kinase A. J Biol Chem 2001; 29: 29.
14. Morrow VA, Foufelle F, Connell JM, Petrie JR, Gould GW, Salt IP. Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J Biol Chem 2003; 278: 31629-39.
15. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-5.
16. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 399: 597-601.
17. Munzel T, Feil R, Mulsch A, Lohmann SM, Hofmann F, Walter U. Physiology and pathophysiology of vascular signaling controlled by guanosine 3′,5′-cyclic monophosphate-dependent protein kinase [corrected]. Circulation 2003; 108: 2172-83.
18. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-12.
19. Sasaki N, Sato T, Ohler A, O'Rourke B, Marban E. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 2000; 101: 439-45.
20. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med 2001; 345: 588-95.
21. Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 1999; 79: 387-423.
22. Schafer A, Wiesmann F, Neubauer S, Eigenthaler M, Bauersachs J, Channon KM. Rapid regulation of platelet activation in vivo by nitric oxide. Circulation 2004; 109: 1819-22.
23. Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 1996; 78: 225-30.
24. Stamler JS, Lamas S, Fang FC. Nitrosylation. the prototypic redox-based signaling mechanism. Cell 2001; 106: 675-83.
25. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109 Suppl: S81-96.
26. Moncada S, Erusalimsky JD. Does nitric oxide modulate mitochondrial energy generation and apoptosis? Nat Rev Mol Cell Biol 2002; 3: 214-20.
27. Halcox JP, Narayanan S, Cramer-Joyce L, Mincemoyer R, Quyyumi AA. Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation. Am J Physiol Heart Circ Physiol 2001; 280: H2470-7.
28. Mombouli JV, Vanhoutte PM. Endothelium-derived hyperpolarizing factor(s): Updating the unknown. Trends Pharmacol Sci 1997; 18: 252-6
29. Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23: 374-80.
30. Moncada S, Higgs EA, Vane JR. Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation. Lancet 1977; 1: 18-20.
31. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. Jama 2001; 286: 954-9.
32. Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: Nested case-control study. Lancet 2005; 365: 475-81.
33. Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc Pharmacol 1998; 32(Suppl 3): S2-13.
34. Marasciulo FL, Montagnani M, Potenza MA. Endothelin-1: The yin and yang on vascular function. Curr Med Chem 2006; 13: 1655-65.
35. Davidge ST. Prostaglandin H synthase and vascular function. Circ Res 2001; 89: 650-60.
36. Lever AF, Lyall F, Morton JJ, Folkow B. Angiotensin II, vascular structure and blood pressure. Kidney Int Suppl 1992; 37: S51-5.
37. Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF, Hamilton CA. Superoxide anion production is increased in a model of genetic hypertension: Role of the endothelium. Hypertension 1999; 33: 1353-8.
38. Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002; 288: 2579-88.
39. Gimbrone MA, Jr. Vascular endothelium: An integrator of pathophysiologic stimuli in atherosclerosis. Am J Cardiol 1995; 75: 67B-70B.
40. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997; 17: 2479-88.
41. Cosentino F, Patton S, d'Uscio LV, Werner ER, Werner-Felmayer G, Moreau P, et al. Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest 1998; 101: 1530-7.
42. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003; 111: 1201-9.
43. Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 1992; 5: 834-42.
44. Baron AD. Hemodynamic actions of insulin. Am J Physiol 1994; 267: E187-202.
45. Baron AD, Steinberg H, Brechtel G, Johnson A. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol 1994; 266: E248-53.
46. Baron AD, Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest 1995; 96: 786-92.
47. Baron AD, Clark MG. Role of blood flow in the regulation of muscle glucose uptake. Annu Rev Nutr 1997; 17: 487-99.
48. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev 2007; 28: 463-91.
49. Vincent MA, Dawson D, Clark AD, Lindner JR, Rattigan S, Clark MG, et al. Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow. Diabetes 2002; 51: 42-8.
50. Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diab Rep 2003; 3: 279-88.
51. Baron AD, Brechtel-Hook G, Johnson A, Cronin J, Leaming R, Steinberg HO. Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. Am J Physiol 1996; 271: E1067-72.
52. Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: Evidence for capillary recruitment. Diabetes 1997; 46: 1381-8.
53. Dawson D, Vincent MA, Barrett EJ, Kaul S, Clark A, Leong-Poi H, et al. Vascular recruitment in skeletal muscle during exercise and hyperinsulinemia assessed by contrast ultrasound. Am J Physiol Endocrinol Metab 2002; 282: E714-20.
54. Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, et al. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 2004; 53: 1418-23.
55. Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, et al. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 2001; 50: 2682-90.
56. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172-9.
57. Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: Physiology or pharmacology? Diabetologia 1998; 41: 369-79.
58. Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, et al. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation 1999; 100: 820-5.
59. Eringa EC, Stehouwer CD, van Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P. Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol 2004; 287: H2043-8.
60. Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol 2005; 289: H813-22.
61. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 1991; 87: 2246-52.
62. Sartori C, Trueb L, Nicod P, Scherrer U. Effects of sympathectomy and nitric oxide synthase inhibition on vascular actions of insulin in humans. Hypertension 1999; 34: 586-9.
63. Creager MA, Liang CS, Coffman JD. Beta adrenergic-mediated vasodilator response to insulin in the human forearm. J Pharmacol Exp Ther 1985; 235: 709-14.
64. Vierhapper H. Effect of exogenous insulin on blood pressure regulation in healthy and diabetic subjects. Hypertension 1985; 7: II49-53.
65. Simionescu M, Gafencu A, Antohe F. Transcytosis of plasma macromolecules in endothelial cells: A cell biological survey. Microsc Res Tech 2002; 57: 269-88.
66. Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894-8.
67. Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is Independent of Ca++ but Requires phosphorylation by Akt at Ser1179. J Biol Chem 2001; 276: 30392-8.
68. Hartell NA, Archer HE, Bailey CJ. Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol 2005; 69: 781-90.
69. Nystrom FH, Quon MJ. Insulin signalling: Metabolic pathways and mechanisms for specificity. Cell Signal 1999; 11: 563-74.
70. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806.
71. Li G, Barrett EJ, Wang H, Chai W, Liu Z. Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells. Endocrinology 2005; 146: 4690-6.
72. Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000; 101: 1539-45.
73. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol 2002; 16: 1931-42.
74. Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 2005; 11: 1188-96.
75. Takahashi S, Mendelsohn ME. Synergistic activation of endothelial nitric-oxide synthase (eNOS) by HSP90 and Akt: Calcium-independent eNOS activation involves formation of an HSP90-Akt-CaM-bound eNOS complex. J Biol Chem 2003; 278: 30821-7.
76. Mount PF, Kemp BE, Power DA. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 2007; 42: 271-9.
77. Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 2001; 88: E68-75.
78. Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 2004; 109: 399-405.
79. Iida S, Taguchi H, Watanabe N, Kushiro T, Kanmatsuse K. Insulin-induced relaxation of rat mesenteric artery is mediated by Ca(2+)-activated K(+) channels. Eur J Pharmacol 2001; 411: 155-160.
80. Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev 2005; 57: 217-52.
81. Kahn NN, Bauman WA, Hatcher VB, Sinha AK. Inhibition of platelet aggregation and the stimulation of prostacyclin synthesis by insulin in humans. Am J Physiol 1993; 265: H2160-7.
82. Osanai T, Fujita N, Fujiwara N, Nakano T, Takahashi K, Guan W, et al. Cross talk of shear-induced production of prostacyclin and nitric oxide in endothelial cells. Am J Physiol Heart Circ Physiol 2000; 278: H233-8.
83. Sobrevia L, Nadal A, Yudilevich DL, Mann GE. Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol 1996; 490 (Pt 3): 775-81.
84. Potenza MA, Marasciulo FL, Tarquinio M, Quon MJ, Montagnani M. Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance. Diabetes 2006; 55: 3594-603.
85. Chisalita SI, Arnqvist HJ. Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells. Diabetologia 2005; 48: 2155-61.
86. Trovati M, Massucco P, Mattiello L, Costamagna C, Aldieri E, Cavalot F, et al. Human vascular smooth muscle cells express a constitutive nitric oxide synthase that insulin rapidly activates, thus increasing guanosine 3′:5′-cyclic monophosphate and adenosine 3′:5′-cyclic monophosphate concentrations. Diabetologia 1999; 42: 831-9.
87. Bergandi L, Silvagno F, Russo I, Riganti C, Anfossi G, Aldieri E, et al. Insulin stimulates glucose transport via nitric oxide/ cyclic GMP pathway in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003; 23: 2215-21.
88. Begum N, Ragolia L, Rienzie J, McCarthy M, Duddy N. Regulation of mitogen-activated protein kinase phosphatase-1 induction by insulin in vascular smooth muscle cells. Evaluation of the role of the nitric oxide signaling pathway and potential defects in hypertension. J Biol Chem 1998; 273: 25164-70.
89. Trovati M, Massucco P, Mattiello L, Cavalot F, Mularoni E, Hahn A, et al. Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: A mechanism potentially involved in insulin-induced modulation of vascular tone. Diabetologia 1995; 38: 936-41.
90. Standley PR, Zhang F, Ram JL, Zemel MB, Sowers JR. Insulin attenuates vasopressin-induced calcium transients and a voltage-dependent calcium response in rat vascular smooth muscle cells. J Clin Invest 1991; 88: 1230-6.
91. Kahn AM, Seidel CL, Allen JC, O'Neil RG, Shelat H, Song T. Insulin reduces contraction and intracellular calcium concentration in vascular smooth muscle. Hypertension 1993; 22: 735-42.
92. Saito F, Hori MT, Fittingoff M, Hino T, Tuck ML. Insulin attenuates agonist-mediated calcium mobilization in cultured rat vascular smooth muscle cells. J Clin Invest 1993; 92: 1161-7.
93. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420: 629-35.
94. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271: 20246-9.
95. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996; 273: 245-8.
96. Begum N, Sandu OA, Duddy N. Negative regulation of rho signaling by insulin and its impact on actin cytoskeleton organization in vascular smooth muscle cells: Role of nitric oxide and cyclic guanosine monophosphate signaling pathways. Diabetes 2002; 51: 2256-63.
97. Lee JH, Ragolia L. AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. Am J Physiol Cell Physiol 2006; 291: C1355-65.
98. Muniyappa R, Walsh MF, Rangi JS, Zayas RM, Standley PR, Ram JL, et al. Insulin like growth factor 1 increases vascular smooth muscle nitric oxide production. Life Sci 1997; 61: 925-31.
99. Touyz RM, Tolloczko B, Schiffrin EL. Insulin attenuates agonist-evoked calcium transients in vascular smooth muscle cells. Hypertension 1994; 23: I25-8.
100. Kahn AM, Lichtenberg RA, Allen JC, Seidel CL, Song T. Insulin-stimulated glucose transport inhibits Ca2+ influx and contraction in vascular smooth muscle. Circulation 1995; 92: 1597-603.
101. Berweck S, Thieme H, Lepple-Wienhues A, Helbig H, Wiederholt M. Insulin-induced hyperpolarization in retinal capillary pericytes. Invest Ophthalmol Vis Sci 1993; 34: 3402-7.
102. Tirupattur PR, Ram JL, Standley PR, Sowers JR. Regulation of Na+,K(+)-ATPase gene expression by insulin in vascular smooth muscle cells. Am J Hypertens 1993; 6: 626-9.
103. Wiecha J, Reineker K, Reitmayer M, Voisard R, Hannekum A, Mattfeldt T, et al. Modulation of Ca2+-activated K+ channels in human vascular cells by insulin and basic fibroblast growth factor. Growth Horm IGF Res 1998; 8: 175-81.
104. Touyz RM, Schiffrin EL. Tyrosine kinase signaling pathways modulate angiotensin II-induced calcium ([Ca2+]i) transients in vascular smooth muscle cells. Hypertension 1996; 27: 1097-103.
105. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 2003; 278: 39422-7.
106. Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, et al. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005; 48: 1229-37.
107. Brownsey RW, Boone AN, Allard MF. Actions of insulin on the mammalian heart: Metabolism, pathology and biochemical mechanisms. Cardiovasc Res 1997; 34: 3-24.
108. Sundell J, Knuuti J. Insulin and myocardial blood flow. Cardiovasc Res 2003; 57: 312-9.
109. von Lewinski D, Bruns S, Walther S, Kogler H, Pieske B. Insulin causes [Ca2+]i-dependent and [Ca2+]i-independent positive inotropic effects in failing human myocardium. Circulation 2005; 111: 2588-95.
110. McDowell SA, McCall E, Matter WF, Estridge TB, Vlahos CJ. Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes. Am J Physiol Heart Circ Physiol 2004; 286: H796-805.
111. Rota M, Boni A, Urbanek K, Padin-Iruegas ME, Kajstura TJ, Fiore G, et al. Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ Res 2005; 97: 1332-41.
112. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 2005; 115: 2108-18.
113. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, et al. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 2003; 100: 12355-60.
114. ] Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: The roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 2002; 105: 1497-502.
115. Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 2002; 109: 629-39.
116. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 2006; 7: 589-600.
117. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.
118. Kylin E. Studien. Hypertonie-Hyperglykamie-Hyperurikamiesyndrome. Zentralblatt fur innere Medizin 1923; 44.
119. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-94.
120. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Jama 2002; 288: 2709-16.
121. Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005; 54: 1615-25.
122. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888-904.
123. King GL. The role of hyperglycaemia and hyperinsulinaemia in causing vascular dysfunction in diabetes. Ann Med 1996; 28: 427-32.
124. Kim JA, Koh KK, Quon MJ. The union of vascular and metabolic actions of insulin in sickness and in health. Arterioscler Thromb Vasc Biol 2005; 25: 889-91.
125. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000; 105: 311-20.
126. Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999; 104: 447-57.
127. Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002; 277: 1794-9.
128. Bursztyn M, Ben-Ishay D, Gutman A. Insulin resistance in spontaneously hypertensive rats but not in deoxycorticosterone-salt or renal vascular hypertension. J Hypertens 1992; 10: 137-42.
129. Lembo G, Iaccarino G, Vecchione C, Rendina V, Trimarco B. Insulin modulation of vascular reactivity is already impaired in prehypertensive spontaneously hypertensive rats. Hypertension 1995; 26: 290-3.
130. Fujishima S, Ohya Y, Nakamura Y, Onaka U, Abe I, Fujishima M. Troglitazone, an insulin sensitizer, increases forearm blood flow in humans. Am J Hypertens 1998; 11: 1134-7.
131. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001; 37: 1344-50.
132. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188-93.
133. Giugliano D, De Rosa N, Di Maro G, Marfella R, Acampora R, Buoninconti R, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993; 16: 1387-90.
134. Panunti B, Kunhiraman B, Fonseca V. The impact of antidiabetic therapies on cardiovascular disease. Curr Atheroscler Rep 2005; 7: 50-7.
135. Lipscombe LL, Gomes T, Levesque LE, Hux JE, Juurlink DN, Alter DA. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007; 298: 2634-43.
136. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595-9.
137. Monzillo LU, Hamdy O, Horton ES, Ledbury S, Mullooly C, Jarema C, et al. Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes Res 2003; 11: 1048-54.
138. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial. JAMA 2004; 292: 1440-6.
139. Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res 2008; 79: 238-48.
140. Davidoff AJ. Convergence of glucose- and fatty acid-induced abnormal myocardial excitation-contraction coupling and insulin signalling. Clin Exp Pharmacol Physiol 2006; 33: 152-8.
141. Liu GX, Hanley PJ, Ray J, Daut J. Long-chain acyl-coenzyme A esters and fatty acids directly link metabolism to K(ATP) channels in the heart. Circ Res 2001; 88: 918-24.
142. Lamounier-Zepter V, Ehrhart-Bornstein M, Karczewski P, Haase H, Bornstein SR, Morano I. Human adipocytes attenuate cardiomyocyte contraction: Characterization of an adipocyte-derived negative inotropic activity. Faseb J 2006; 20: 1653-9.
143. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: The search for a unifying hypothesis. Circ Res 2006; 98: 596-605.
144. Setty S, Sun W, Tune JD. Coronary blood flow regulation in the prediabetic metabolic syndrome. Basic Res Cardiol 2003; 98: 416-23.
145. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001; 108: 1341-8.
146. Montagnani M. Diabetic cardiomyopathy: How much does it depend on AGE? Br J Pharmacol 2008; 154: 725-6.
147. NIH Consensus Conference. Impotence. NIH Consensus Conference Development Panel on Impotence. Jama 1993; 270: 83-90.
148. McVary KT. Clinical practice. Erectile dysfunction. N Engl J Med 2007; 357: 2472-81.
149. Christ GJ, Lue T. Physiology and biochemistry of erections. Endocrine 2004; 23: 93-100.
150. Christ GJ, Hodges S. Molecular mechanisms of detrusor and corporal myocyte contraction: Identifying targets for pharmacotherapy of bladder and erectile dysfunction. Br J Pharmacol 2006; 147(Suppl 2): S41-55.
151. Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, Bank AJ. Impaired brachial artery endothelium-dependent and - independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004; 43: 179-84.
152. Fonseca V, Jawa A. Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: Common pathways and treatments? Am J Cardiol 2005; 96: 13M-18M.
153. Billups KL, Bank AJ, Padma-Nathan H, Katz S, Williams R. Erectile dysfunction is a marker for cardiovascular disease: Results of the minority health institute expert advisory panel. J Sex Med 2005; 2: 40-50; discussion 50-2.
154. Chiurlia E, D'Amico R, Ratti C, Granata AR, Romagnoli R, Modena MG. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 2005; 46: 1503-6.
155. Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003; 44: 360-4; discussion 364-5.
156. Montorsi P, Ravagnani PM, Galli S, Rotatori F, Veglia F, Briganti A, et al. Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: The COBRA trial. Eur Heart J 2006; 27: 2632-9.
157. Christ GJ, Hsieh Y, Zhao W, Schenk G, Venkateswarlu K, Wang HZ, et al. Effects of streptozotocin-induced diabetes on bladder and erectile (dys)function in the same rat in vivo. BJU Int 2006; 97: 1076-82.
158. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61.
159. Fedele D, Coscelli C, Cucinotta D, Forti G Santeusanio F, Viaggi S, et al. Incidence of erectile dysfunction in Italian men with diabetes. J Urol 2001; 166: 1368-71.
160. Christ GJ. The penis as a vascular organ. The importance of corporal smooth muscle tone in the control of erection. Urol Clin North Am 1995; 22: 727-45.
161. Anfossi G, Massucco P, Mattiello L, Balbo A, Russo I, Doronzo G, et al. Insulin influences the nitric oxide cyclic nucleotide pathway in cultured human smooth muscle cells from corpus cavernosum by rapidly activating a constitutive nitric oxide synthase. Eur J Endocrinol 2002; 147: 689-700.
162. Li H, Xu L, Dunbar JC, Dhabuwala CB, Sima AA. Effects of C-peptide on expression of eNOS and iNOS in human cavernosal smooth muscle cells. Urology 2004; 64: 622-7.
163. Huang LC, Heimark D, Linko J, Nolan R, Larner J. A model phosphatase 2C - > phosphatase 1 activation cascade via dual control of inhibitor-1 (INH-1) and DARPP-32 dephosphorylation by two inositol glycan putative insulin mediators from beef liver. Biochem Biophys Res Commun 1999; 255: 150-6.
164. Nascimento NR, Lessa LM, Kerntopf MR, Sousa CM, Alves RS, Queiroz MG, et al. Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide. Proc Natl Acad Sci USA 2006; 103: 218-23.
165. Myung SC, Keum EM, Park SY, Lee MY, Kim SC. Vasomotor action of insulin on the rabbit normal cavernous smooth muscle. Eur J Pharmacol 2006; 536: 142-7.
166. Pu XY, Wang XH, Gao WC, Yang ZH, Li SL, Wang HP, et al. Insulin-like growth factor-1 restores erectile function in aged rats: modulation the integrity of smooth muscle and nitric oxide-cyclic guanosine monophosphate signaling activity. J Sex Med 2008; 5: 1345-54.
167. Gholamine B, Shafiei M, Motevallian M, Mahmoudian M. Effects of pioglitazone on erectile dysfunction in sildenafil poor-responders: A randomized, controlled study. J Pharm Pharm Sci 2008; 11: 22-31.