Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-Kinase signaling hyperactivation

Journal of Sexual Medicine

Volumn 6, Issue 1, 2009, Pages 91-106

  Morelli, Annamaria ^a   Chavalmane, Aravinda Krishnappa ^a   Filippi, Sandra ^a   Fibbi, Benedetta ^a   Silvestrini, Enrico ^a   Sarchielli, Erica ^a   Zhang, Xin Hua ^a   Vignozzi, Linda ^a   Vannelli, Gabriella Barbara ^a   Forti, Gianni ^a   Maggi, Mario ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

Author keywords

Diabetes; Erectile Dysfunction; Penile Smooth Muscle Cells; RhoA Dependent Functions; ROCK Activity

Indexed keywords

ATORVASTATIN; GERANYLGERANYL PYROPHOSPHATE; LIPID; RHO KINASE; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SILDENAFIL;

ALLOXAN DIABETES MELLITUS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL MIGRATION; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DIABETES MELLITUS; DOWNSTREAM PROCESSING; DRUG EFFICACY; DRUG POTENTIATION; ELECTROSTIMULATION; ENZYME ACTIVATION; ERECTILE DYSFUNCTION; GENE EXPRESSION; GENE TRANSLOCATION; HYPERGLYCEMIA; HYPOGONADISM; LIPID BLOOD LEVEL; MALE; NONHUMAN; PENIS ERECTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; RABBIT; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER;

EID: 58149493011     PISSN: 17436095     EISSN: 17436109     Source Type: Journal    
DOI: 10.1111/j.1743-6109.2008.01057.x     Document Type: Article

References (50)

1. Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJ. Endothelial dysfunction in erectile dysfunction: Role of the endothelium in erectile physiology and disease. J Androl 2003;24:S17-37.
2. Cellek S, Foxwell NA, Moncada S. Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2003;52:2353-62.
3. Chang S, Hypolite JA, Velez M, Changolkar A, Wein AJ, Chacko S, DiSanto ME. Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits. Am J Physiol Regul Integr Comp Physiol 2004;287:R950-60.
4. Musicki B, Burnett AL. Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res 2007;19:129-38.
5. Chang S, Hypolite JA, Changolkar A, Wein AJ, Chacko S, DiSanto ME. Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase beta. Int J Impot Res 2003;15:53-62.
6. Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJ, Kadowitz PJ. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA 2004;101:9121-6.
7. Vignozzi L, Morelli A, Filippi S, Ambrosini S, Mancina R, Luconi M, Mungai S, Vannelli GB, Zhang XH, Forti G, Maggi M. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 2007;4:620-32.
8. Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett 2001;165:1-10.
9. Ren XD, Kiosses WB, Schwartz MA. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J 1999;18:578-85.
10. Wheeler AP, Ridley AJ. Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp Cell Res 2004;301:43-9.
11. Barlow CA, Rose P, Pulver-Kaste RA, Lounsbury KM. Excitation-transcription coupling in smooth muscle. J Physiol 2006;570:59-64.
12. Hinson JS, Medlin MD, Lockman K, Taylor JM, Mack CP. Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors. Am J Physiol Heart Circ Physiol 2007;292:H1170-80.
13. McDonald OG, Wamhoff BR, Hoofnagle MH, Owens GK. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest 2006;116:36-48.
14. Wang Z, Wang DZ, Pipes GC, Olson EN. Myocardin is a master regulator of smooth muscle gene expression. Proc Natl Acad Sci USA 2003;100:7129-34.
15. Costabile RA. Optimizing treatment for diabetes mellitus induced erectile dysfunction. J Urol 2003;170:S35-398.
16. Vickers MA, Wright EA. Erectile dysfunction in the patient with diabetes mellitus. Am J Manag Care 2004;10:S3-11; quiz S12-6.
17. Suetomi T, Kawai K, Hinotsu S, Joraku A, Oikawa T, Sekido N, Miyanaga N, Shimazui T, Akaza H. Negative impact of metabolic syndrome on the responsiveness to sildenafil in Japanese men. J Sex Med 2008;5:1443-50.
18. Corona G, Mannucci E, Petrone L, Balercia G, Paggi F, Fisher AD, Lotti F, Chiarini V, Fedele D, Forti G, Maggi M. NCEP-ATPIII-defined metabolic syndrome, type 2 diabetes mellitus, and prevalence of hypogonadism in male patients with sexual dysfunction. J Sex Med 2007;4:1038-45.
19. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering-are they clinically relevant? Eur Heart J 2003;24:225-48.
20. Rikitake Y, Liao JK, Rho GT. Pases, statins, and nitric oxide. Circ Res 2005;97:1232-5.
21. Fibbi B, Morelli A, Marini M, Zhang XH, Mancina R, Vignozzi L, Filippi S, Chavalmane A, Silvestrini E, Colli E, Adorini L, Vannelli GB, Maggi M. Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway. J Androl 2008;29:70-84.
22. Granchi S, Vannelli GB, Vignozzi L, Crescioli C, Ferruzzi P, Mancina R, Vinci MC, Forti G, Filippi S, Luconi M, Ledda F, Maggi M. Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells. Mol Hum Reprod 2002;8:1053-64.
23. Abdelbaky TM, Brock GB, Huynh H. Improvement of erectile function in diabetic rats by insulin: Possible role of the insulin-like growth factor system. Endocrinology 1998;139:3143-7.
24. Zhang XH, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, Maggi M. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med 2006;3:253-66.
25. Zhang XH, Morelli A, Luconi M, Vignozzi L, Filippi S, Marini M, Vannelli GB, Mancina R, Forti G, Maggi M. Testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum. Eur Urol 2005;47:409-16.
26. Morelli A, Vignozzi L, Filippi S, Vannelli GB, Ambrosini S, Mancina R, Crescioli C, Donati S, Fibbi B, Colli E, Adorini L, Maggi M. BXL-628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder. Prostate 2007;67:234-47.
27. Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, Orlando C, Vannelli GB, Aversa A, Natali A, Forti G, Giorgi M, Jannini EA, Ledda F, Maggi M. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 2004;145:2253-63.
28. DeLean A, Munson PJ, Rodbard D. Simultaneous analysis of families of sigmoidal curves: Application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol 1978;235:E97-102.
29. Dorfman VB, Lopez-Costa JJ, Vega C, Bayona JC, Capani F, Fabian Loidl C, Coirini H. Changes of NADPH-diaphorase reactivity in lumbar spinal cord of short-term streptozotocin induced diabetic rats. Brain Res 2004;997:185-93.
30. Ballester J, Munoz MC, Dominguez J, Rigau T, Guinovart JJ, Rodriguez-Gil JE. Insulin-dependent diabetes affects testicular function by FSH- and LH-linked mechanisms. J Androl 2004;25:706-19.
31. Melman A. Pathophysiologic basis of erectile dysfunction. What can we learn from animal models? Int J Impot Res 2001;13:140-2.
32. Tanaka M, Nakaya S, Kumai T, Watanabe M, Matsumoto N, Kobayashi S. Impaired testicular function in rats with diet-induced hypercholesterolemia and/or streptozotocin-induced diabetes mellitus. Endocr Res 2001;27:109-17.
33. Van Linthout S, Riad A, Dhayat N, Spillmann F, Du J, Dhayat S, Westermann D, Hilfiker-Kleiner D, Noutsias M, Laufs U, Schultheiss HP, Tschope C. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia 2007;50:1977-86.
34. Chrissobolis S, Sobey CG. Recent evidence for an involvement of rho-kinase in cerebral vascular disease. Stroke 2006;37:2174-80.
35. Hartshorne DJ, Ito M, Erdodi F. Role of protein phosphatase type 1 in contractile functions: Myosin phosphatase. J Biol Chem 2004;279:37211-4.
36. Mack CP, Somlyo AV, Hautmann M, Somlyo AP, Owens GK. Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem 2001;276:341-7.
37. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995;75:487-517.
38. Wamhoff BR, Bowles DK, McDonald OG, Sinha S, Somlyo AP, Somlyo AV, Owens GK. L-type voltage-gated Ca2+ channels modulate expression of smooth muscle differentiation marker genes via a rho kinase/myocardin/ SRF-dependent mechanism. Circ Res 2004;95:406-14.
39. Tanaka T, Nishimura D, Wu RC, Amano M, Iso T, Kedes L, Nishida H, Kaibuchi K, Hamamori Y. Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. J Biol Chem 2006;281:15320-9.
40. Posern G, Treisman R. Actin' together: Serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol 2006;16:588-96.
41. Porter KE, Turner NA, O'Regan DJ, Balmforth AJ, Ball SG. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res 2004;61:745-55.
42. Danesh FR, Sadeghi MM, Amro N, Philips C, Zeng L, Lin S, Sahai A, Kanwar YS. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: Implications for diabetic nephropathy. Proc Natl Acad Sci USA 2002;99:8301-5.
43. Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 1997;272:31725-9.
44. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129-35.
45. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000;6:1004-10.
46. Feron O, Dessy C, Desager JP, Balligand JL. Hydroxy-methylglutaryl-coenzyme a reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 2001;103:113-8.
47. Chitaley K, Wingard CJ, Clinton Webb, Branam R, Stopper H, Lewis VS, Mills RW, TM. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 2001;7:119-22.
48. Lee DL, Webb RC, Jin L. Hypertension and RhoA/Rho-kinase signaling in the vasculature: Highlights from the recent literature. Hypertension 2004;44:796-9.
49. Herrmann HC, Levine LA, Macaluso J, Jr, Walsh, M, Bradbury D, Schwartz S, Mohler ER 3rd, Kimmel SE. Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results. J Sex Med 2006;3:303-8.
50. Miner M, Gilderman L, Bailen J, Cook D, Dawson K, Stanislaus M, Beresford E, Barnes A. Vardenafil in men with stable statin therapy and dyslipidemia. J Sex Med 2008;5:1455-63.