Tadalafil attenuates graft arteriosclerosis of aortic transplant in a rat model

Document Type : Original Article


Transplantation Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China


Objective(s): Tadalafil can restore endothelial function and treat atherosclerosis. However, the effect of tadalafil on transplant arteriosclerosis remains unclear. In this study, we explore the effects of tadalafil on allograft vasculopathy.
Materials and Methods: Male Brow-Norway rats supplied aorta grafts for Male Lewis rats. All recipients were divided into 3 groups: saline as placebo (control) treated group, low dose tadalafil (0.5 mg/kg/day) treated group, and high dose tadalafil (1.0 mg/kg/day) treated group. Eight weeks after transplantation, the grafts were harvested at and analyzed by histological and Western blot analysis. An enzyme-linked immunosorbent assay (ELISA) was used for measure of plasma cyclic guanylate monophosphate (cGMP).
Results:the treatment with tadalafil significantly alleviated the neointimal thickness of aortas compared with the control group (P<0.05). Tadalafil also remarkably enhanced the production of cGMP in plasma and expression of cGMP-dependent kinase I (PKG-I) and RhoA compared with control group (P<0.05).
Conclusion: These results showed that tadalafil can attenuate graft arteriosclerosis by cGMP -PKG-I pathway.


1. Von Rossum A, Laher I, Choy JC. Immune-mediated vascular injury and dysfunction in transplant arteriosclerosis. Front Immunol 2015; 5:684.
2. Qin L, Yu L, Min W. Mouse models for graft arteriosclerosis. J Vis Exp 2013; e50290-e50290.
3. Tiefenbacher C, Kreuzer J. Nitric oxide-mediated endothelial dysfunction-Is there need to treat? Curr Vasc Pharmacol 2003; 1:123-133.
4. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685-1695.
5. Cerrito MG, Scagliarini A, Froio A, Liloia A, Busnelli M, Giovannoni R, et al. Heme oxygenase-1 inhibition prevents intimal hyperplasia enhancing nitric oxide-dependent apoptosis of vascular smooth muscle cells. Biol Pharm Bull 2011; 34:1204-1214.
6. Schofield RS, Edwards DG, Schuler BT, Estrada J, Aranda JM, Pauly DF, et al. Vascular effects of sildenafil in hypertensive cardiac transplant recipients. Am J Hyper 2003; 16:874-877.
7. Balarini CM, Leal MA, Gomes IB, Pereira TM, Gava AL, Meyrelles SS, et al. Sildenafil restores endothelial function in the apolipoprotein E knockout mouse. J Transl Med 2013; 11:10.1186.
8. Mostafa ME, Senbel AM, Mostafa T. Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats. Urology 2013; 81:1253-1260.
9. Onuta G, Rienstra H, de Boer JF, Boer MW, Roks AJ, Klatter FA, et al. Rosiglitazone attenuates transplant arteriosclerosis after allogeneic aorta transplantation in rats. Transplantation 2007; 84:517-526.
10. Lee PC, Wang ZL, Qian S, Watkins SC, Lizonova A, Kovesdi I, et al. Endothelial nitric oxide synthase protects aortic allografts from the development of transplant arteriosclerosis. Transplantation 2000; 69:1186-1192.
11. Maimaitiyiming H, Li Y, Cui W, Tong X, Norman H, Qi X, et al. Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function. Am J Physiol Renal Physiol 2013; 305:F881-F890.
12. Tang J, Fitzgerald SM, Boughtman BN, Cole SW, Brands MW, Zhang JH. Decreased RhoA expression in myocardium of diabetic rats. Canad J Physiol Pharmacol 2005; 83:775-783.
13. Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, et al. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab 2004; 24:1133-1145.
14. Libby P, Pober JS. Chronic rejection. Immunity 2001; 14:387-397.
15. Osto E, Tona F, Bon ED, Iliceto S, Cella G. Endothelial dysfunction in cardiac allograft vasculopathy: potential pharmacological interven-tions. Curr Vasc Pharmacol 2010; 8:169-188.
16. Lietz K, Miller LW. Current understanding and management of allograft vasculopathy. Semi Thorac  Cardiovasc Surg 2004; 16:386-394.
17. Ahmad A, Khan RM, Alkharfy KM. Effects of selected bioactive natural products on the vascular endothelium. J Cardiovasc Pharmacol 2003; 62:111-121.
18. Colvin-Adams M, Harcourt N, Duprez D. Endothelial dysfunction and cardiac allograft vasculopathy. J Cardiovasc Transl Res 2013; 6:263-277.
19. Chen J, Crossland RF, Noorani MM, Marrelli SP. Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation. Am J Physiol Heart Circ Physiol 2009; 297:417-424.
20. Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, et al. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Iβ. Nature 2000; 404:197-201.
21. Tomasoni L, Sitia S, Borghi C, Cicero A, Ceconi C, Cecaro F, et al. Effects of treatment strategy on endothelial function. Autoimmun Rev 2010; 9:840-844.
22. Russo I, Del Mese P, Doronzo G, Mattiello L, Viretto M, Bosia A, et al. Resistance to the nitric oxide/cyclic guanosine 5'-monophosphate/protein kinase G pathway in vascular smooth muscle cells from the obese Zucker rat, a classical animal model of insulin resistance: role of oxidative stress. Endocrinology 2008; 149:1480-1489.
23. Loganathan S, Radovits T, Hirschberg K,Korkmaz S, Barnucz E, Karck M, et al. Effects of selective phosphodiesterase-5-inhibition on myocardial contrac-
tility and reperfusion injury after heart transplantation. Transplantation 2008; 86:1414-1418.
24. Koupparis AJ, Jeremy JY, Muzaffar S, Persad R, Shukla N. Sildenafil inhibits the formation of superoxide and the expression of gp47phox NAD [P] H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells. BJU Int 2005; 96:423-427.
25. Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis Essential role of nitric oxide signaling. J Biol Chem 2005; 280:12944-12955.
26. Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005; 25:1767-1775.
27. Kato M, Blanton R, Wang G-R, Judson TJ, Abe Y, Myoishi M, et al. Direct binding and regulation of RhoA protein by cyclic GMP-dependent protein kinase Iα. J Biol Chem 2012; 287:41342-41351.
28. Hrometz SL, Shields KM. Sildenafil citrate for the treatment of pulmonary hypertension. Drugs Today 2006; 42:771-784.