Potential use of angiotensin receptor blockers in skin pathologies

Document Type : Review Article

Authors

1 Department of Physiology, Pharmacology and Medical Physic, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

2 Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran

3 Department of Cardiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

4 Student of School of Veterinary Medicine, Faculty of Veterinary Medicine, University of Shahrekord, Shahrekord, Iran

5 Department of Veterinary Surgery, Science and Research Branch, Islamic Azad University, Tehran, Iran

6 Department of Dermatology, University of Massachusetts School of Medicine, Worchester, MA, USA

7 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Renin-angiotensin system (RAS) components such as angiotensin II, angiotensin receptors (AT1R and AT2R), and angiotensin-converting enzyme (ACE) are expressed in different cell types of the skin. Through AT1R, angiotensin II increases proinflammatory cytokines contributing to fibrosis, angiogenesis, proliferation, and migration of immune cells to the skin. In contrast, AT2R suppresses the effects mentioned above. Many studies show that angiotensin receptor blockers (ARBs) and angiotensin-converting enzymes (ACEi) reduce the proinflammatory cytokines and fibrogenic factors including transforming growth factor β (TGF-β), Connective tissue growth factor (CTGF), and IL-6. This review article provides a detailed research study on the implications of ARBs in wound healing, hypertrophic scar, and keloids. We further discuss the therapeutic potentials of ARBs in autoimmune and autoinflammatory skin diseases and cancer, given their anti-fibrotic and anti-inflammatory effects.

Keywords


1. Drosten M, Lechuga C, Barbacid MJO. Ras signaling is essential for skin development. Oncogene 2014; 33:2857-2865.
2. Silva IMS, Assersen KB, Willadsen NN, Jepsen J, Artuc M, Steckelings UMJED. The role of the renin‐angiotensin system in skin physiology and pathophysiology. Exp Dermatol 2020; 29:891-901.
3. Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader MJAJoP-H, et al. The renin-angiotensin system: Going beyond the classical paradigms. Am J Physiol Heart Circ Physiol 2019; 316:H958-H970.
4. Hedayatyanfard K, Haddadi NS, Ziai SA, Karim H, Niazi F, Steckelings UM, et al. The renin‐angiotensin system in cutaneous hypertrophic scar and keloid formation. Exp Dermatol 2020; 29:902-909.
5. Ellis S, Lin EJ, Tartar DJCdr. Immunology of wound healing. Curr Dermatol Rep 2018; 7:350-358.
6. Hedayatyanfard K, Khoulenjani SB, Abdollahifar MA, Amani D, Habibi B, Zare F, et al. Chitosan/PVA/Doxycycline film and nanofiber accelerate diabetic wound healing in a rat model. Iran J Pharm Res 2020; 19:225-239.
7. Jadhav SS, Sharma N, Meeks CJ, Mordwinkin NM, Espinoza TB, Roda NR, et al. Effects of combined radiation and burn injury on the renin–angiotensin system. Wound Repair Regen 2013; 21:131-140.
8. Rodgers K, Xiong S, Felix J, Roda N, Espinoza T, Maldonado S, et al. Development of angiotensin (1‐7) as an agent to accelerate dermal repair. Wound Repair Regen 2001; 9:238-247.
9. Takeda H, Katagata Y, Hozumi Y, Kondo SJTAjop. Effects of angiotensin II receptor signaling during skin wound healing. Am J Pathol 2004; 165:1653-1662.
10. Yahata Y, Shirakata Y, Tokumaru S, Yang L, Dai X, Tohyama M, et al. A novel function of angiotensin II in skin wound healing: induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated EGF receptor transactivation. J Biol Chem 2006; 281:13209-13216.
11. Sakai H, Matsuura K, Tanaka Y, Honda T, Nishida T, Inui MJMP. Signaling mechanism underlying the promotion of keratinocyte migration by angiotensin II. Mol Pharmacol 2015; 87:277-285.
12. Kamber M, Papalazarou V, Rouni G, Papageorgopoulou E, Papalois A, Kostourou V. Angiotensin II inhibitor facilitates epidermal wound regeneration in diabetic mice. Front Physiol 2015; 6:170.
13. Marin S, Godet I, Nidadavolu LS, Tian J, Dickinson LE, Walston JD, et al. Valsartan and sacubitril combination treatment enhances collagen production in older adult human skin cells. Exp Gerontol 2022;165:111835.
14. Abadir P, Hosseini S, Faghih M, Ansari A, Lay F, Smith B, et al. Topical reformulation of valsartan for treatment of chronic diabetic wounds. J Invest Dermatol 2018; 138:434-443.
15. Hirt P, Lev‐Tov H. Use of topical valsartan as a novel treatment for complicated leg ulcers. Br J Dermatol 2020; 182:1301-1303.
16. Nidadavolu LS, Stern D, Lin R, Wang Y, Li Y, Wu Y, et al. Valsartan nano‐filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds. Wound Repair Regen 2021; 29:927-937.
17. Mahdavian Delavary B, Van der Veer WM, Ferreira JA, Niessen FBJJops, surgery h. Formation of hypertrophic scars: Evolution and susceptibility. J Plast Surg Hand Surg 2012; 46:95-101.
18. Rupérez Mn, Lorenzo Os, Blanco-Colio LM, Esteban V, Egido Js, Ruiz-Ortega MJC. Connective tissue growth factor is a mediator of angiotensin II–induced fibrosis. Circulation 2003; 108:1499-1505.
19. Liu W, Wang D, Cao YJCgt. TGF-β: A fibrotic factor in wound scarring and a potential target for anti-scarring gene therapy. Curr Gene Ther 2004; 4:123-136.
20. Niazi F, Hedayatyanfard K, Soroush M, Habibi B, Haddadi N-S, Rostami K, et al. Increased level of Histamine in keloid Tissue. Novelty in Biomedicine 2021; 9:1-4.
21. Berman B, Maderal A, Raphael BJDS. Keloids and hypertrophic scars: Pathophysiology, classification, and treatment. Dermatol Surg 2017; 43:S3-S18.
22. Niazi F, Hooshyar SH, Hedayatyanfard K, Ziai SA, Doroodgar F, Niazi S, et al. Detection of angiotensin II and AT1 receptor concentrations in keloid and hypertrophic scar. J Clin Aesthet Dermatol 2018; 11:36.
23. Gira AK, Brown LF, Washington CV, Cohen C, Arbiser JLJJotAAoD. Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol 2004; 50:850-853.
24. Ren M, Hao S, Yang C, Zhu P, Chen L, Lin D, et al. Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues. Diab Vasc Dis Res 2013; 10:426-435.
25. Ulrich D, Ulrich F, Unglaub F, Piatkowski A, Pallua NJJoP, Reconstructive, Surgery A. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with different types of scars and keloids. J Plast Reconstr Aesthet Surg 2010; 63:1015-1021.
26. Zhang T, Wang X-F, Wang Z-C, Lou D, Fang Q-Q, Hu Y-Y, et al. Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomed Pharmacother 2020; 129:110287.
27. Ogawa RJIjoms. Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci 2017; 18:606.
28. Akershoek JJ, Vlig M, Brouwer K, Talhout W, Beelen RH, Middelkoop E, et al. The presence of tissue renin-angiotensin system components in human burn wounds and scars. Burns Open 2018; 2:114-121.
29. Hedayatyanfard K, Ziai SA, Niazi F, Habibi I, Habibi B, Moravvej HJWR, et al. Losartan ointment relieves hypertrophic scars and keloid: A pilot study. Wound Repair Regen 2018; 26:340-343.
30. Zheng B, Fang Q-Q, Wang X-F, Shi B-H, Zhao W-Y, Chen C-Y, et al. The effect of topical ramipril and losartan cream in inhibiting scar formation. Biomed Pharmacother 2019; 118:109394.
31. Hu YY, Fang QQ, Wang XF, Zhao WY, Zheng B, Zhang DD, et al. Angiotensin‐converting enzyme inhibitor and angiotensin II type 1 receptor blocker: Potential agents to reduce post‐surgical scar formation in humans. Basic Clin Pharmacol Toxicol 2020; 127:488-494.
32. Murphy A, LeVatte T, Boudreau C, Midgen C, Gratzer P, Marshall J, et al. Angiotensin II type I receptor blockade is associated with decreased cutaneous scar formation in a rat model. Plast Reconstr Surg 2019; 144:803e-813e.
33. Kurt M, Akoz Saydam F, Bozkurt M, Serin M, Caglar AJJoPS, Surgery H. The effects of valsartan on scar maturation in an experimental rabbit ear wound model. J Plast Surg Hand Surg 2020; 54:382-387.
34. Rompe F, Artuc M, Hallberg A, Alterman M, Ströder K, Thöne-Reineke C, et al. Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor κB. Hypertension 2010; 55:924-931.
35. Tan WQ, Fang QQ, Shen XZ, Giani JF, Zhao TV, Shi P, et al. Angiotensin‐converting enzyme inhibitor works as a scar formation inhibitor by down‐regulating Smad and TGF‐β‐activated kinase 1 (TAK1) pathways in mice. Br J Pharmacol 2018; 175:4239-4252.
36. Wang J, Chen L, Chen B, Meliton A, Liu SQ, Shi Y, et al. Chronic activation of the renin-angiotensin system induces lung fibrosis. Sci Rep 2015; 5:1-11.
37. Min L-J, Cui T-X, Yahata Y, Yamasaki K, Shiuchi T, Liu H-W, et al. Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes. Endocrinology 2004; 145:253-260.
38. Lin YT, Wang HC, Tsai MH, Su YY, Yang MY, Chien CYJC. Angiotensin II receptor blockers valsartan and losartan improve survival rate clinically and suppress tumor growth via apoptosis related to PI3K/AKT signaling in nasopharyngeal carcinoma. Cancer 2021; 127:1606-1619.
39. Herr D, Rodewald M, Fraser H, Hack G, Konrad R, Kreienberg R, et al. Potential role of renin–angiotensin-system for tumor angiogenesis in receptor negative breast cancer. Gynecol Oncol 2008; 109:418-425.
40. Munk VC, Sanchez de Miguel L, Petrimpol M, Butz N, Banfi A, Eriksson U, et al. Angiotensin II induces angiogenesis in the hypoxic adult mouse heart in vitro through an AT2-B2 receptor pathway. Hypertension 2007; 49:1178-1185.
41. Christian JB, Lapane KL, Hume AL, Eaton CB, Weinstock MAJJotNCI. Association of ACE inhibitors and angiotensin receptor blockers with keratinocyte cancer prevention in the randomized VATTC trial. J Natl Cancer Inst 2008; 100:1223-1232.
42. Takeda H, Kondo SJTAjop. Differences between squamous cell carcinoma and keratoacanthoma in angiotensin type-1 receptor expression. Am J Pathol 2001; 158:1633-1637.
43. Moscarelli L, Zanazzi M, Mancini G, Rossi E, Caroti L, Rosso G, et al. Keratinocyte cancer prevention with ACE inhibitors, angiotensin receptor blockers or their combination in renal transplant recipients. Clin Nephrol 2010; 73:439-445.
44. Otake AH, Mattar AL, Freitas HC, Machado CML, Nonogaki S, Fujihara CK, et al. Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma. Cancer Chemother Pharmacol 2010; 66:79-87.
45. Ishikane S, Hosoda H, Nojiri T, Tokudome T, Mizutani T, Miura K, et al. Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells. Biochem Pharmacol 2018; 154:136-147.
46. Egami K, Murohara T, Shimada T, Sasaki K-i, Shintani S, Sugaya T, et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest 2003; 112:67-75.
47. Renziehausen A, Wang H, Rao B, Weir L, Nigro CL, Lattanzio L, et al. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene 2019; 38:2320-2336.
48. Nardone B, Majewski S, Kim AS, Kiguradze T, Martinez-Escala EM, Friedland R, et al. Melanoma and non-melanoma skin cancer associated with angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers and thiazides: A matched cohort study. Drug Saf 2017; 40:249-255.
49. Wolf G, Ziyadeh FN, Thaiss F, Tomaszewski J, Caron RJ, Wenzel U, et al. Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest 1997; 100:1047-1058.
50. Zhao M, Bai M, Ding G, Zhang Y, Huang S, Jia Z, et al. Angiotensin II stimulates the NLRP3 inflammasome to induce podocyte injury and mitochondrial dysfunction. Kidney Dis (Basel) 2018; 4:83-94.
51. Dandona P, Dhindsa S, Ghanim H, Chaudhuri AJJohh. Angiotensin II and inflammation: The effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens 2007; 21:20-27.
52. Kaufman KM, Kelly J, Gray-McGuire C, Asundi N, Yu H, Reid J, et al. Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus. Mol Cell Endocrinol 2001; 177:81-85.
53. Rahmati rm, saeidi m, eshghi gr. Serum angiotensin converting enzyme in patients with psoriasis. Iran J Dermatol 2009; 12:127-130.
54. Abdollahimajd F, Niknezhad N, Haghighatkhah HR, Namazi N, Niknejad N, Talebi AJJotAAoD. Angiotensin-converting enzyme and subclinical atherosclerosis in psoriasis: Is there any association? A case-control study. J Am Acad Dermatol 2020; 82:980-981. e981.
55. Huskić J, Mulabegović N, Alendar F, Ostojić L, Ostojić Z, Šimić D, et al. Serum and tissue angiotensin converting enzyme in patients with psoriasis. Coll Antropol 2008; 32:1215-1219.
56. Song GG, Bae S-C, Kim J-H, Lee YHJJotr-a-as. The angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to rheumatoid arthritis, vitiligo and psoriasis: A meta-analysis. J Renin Angiotensin Aldosterone Syst 2015; 16:195-202.
57. Zeini MS, Haddadi N-S, Shayan M, Zeini MS, Kazemi K, Solaimanian S, et al. Losartan ointment attenuates imiquimod-induced psoriasis-like inflammation. Int Immunopharmacol 2021; 100:108160.
58. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al. Interleukin 17 promotes angiotensin II–induced hypertension and vascular dysfunction. Hypertension 2010; 55:500-507.
59. Mehrotra P, Patel JB, Ivancic CM, Collett JA, Basile DPJKi. Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney Int 2015; 88:776-784.
60. Amisha PM, Pathania M, Rathaur VKJIJoIRiMS. Chronic plaque psoriasis exacerbated by telmisartan therapy: A case report. Int J Innov Res Med Sci 2019; 4:615-617.
61. Kawamura A, Ochiai TJEJoD. Candesartan cilexetil induced pustular psoriasis. Eur J Dermatol 2003; 13:406-407.
62. Lamba G, Palaniswamy C, Singh T, Shah D, Lal S, Vinnakota R, et al. Psoriasis induced by losartan therapy: a case report and review of the literature. Am J Ther 2011; 18:e78-e80.
63. Vincent F, Bourke P, Morand EF, Mackay F, Bossingham DJIMJ. Focus on systemic lupus erythematosus in Indigenous A ustralians: Towards a better understanding of autoimmune diseases. Intern Med J 2013; 43:227-234.
64. Teplitsky V, Shoenfeld Y, Tanay AJL. The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans. Lupus 2006; 15:319-325.
65. Soto M, Delatorre N, Hurst C, Rodgers KEJFii. Targeting the protective arm of the renin-angiotensin system to reduce systemic lupus erythematosus related pathologies in MRL-Lpr mice. Front Immunol 2020; 11:1572.
66. Inamadar ACJDT. Losartan as disease modulating therapy for recessive dystrophic epidermolysis bullosa. Dermatol Ther 2020; 33:e14279.
67. Nyström A, Thriene K, Mittapalli V, Kern JS, Kiritsi D, Dengjel J, et al. Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms. EMBO Mol Med 2015; 7:1211-1228.
68. Cappuccio G, Caiazza M, Roca A, Melis D, Iuliano A, Matyas G, et al. A pilot clinical trial with losartan in Myhre syndrome. Am J Med Genet A 2021; 185:702-709.
69. Kurosaka M, Suzuki T, Hosono K, Kamata Y, Fukamizu A, Kitasato H, et al. Reduced angiogenesis and delay in wound healing in angiotensin II type 1a receptor-deficient mice. Biomed Pharmacother 2009; 63:627-634.
70. Chisholm J, Gareau AJ, Byun S, Paletz JL, Tang D, Williams J, et al. Effect of compound 21, a selective angiotensin II type 2 receptor agonist, in a murine xenograft model of dupuytren disease. Plast Reconstr Surg 2017; 140:686e-696e.
71. Trommer H, Neubert RJSp, physiology. Overcoming the stratum corneum: the modulation of skin penetration. Skin Pharmacol Physiol 2006; 19:106-121.
72. Trbojević JB, Odović J, Trbojević-Stanković J, Nešić DM, Jelić RJAoBS. Relationship between the bioavailability and molecular properties of angiotensin ii receptor antagonists. Arch Biol Sci 2016; 68:273-278.
73. Israili ZJJohh. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000; 14:S73-S86.