Original Article

Efficacy of Optimal Dosage of Lisinopril in Inhibiting Myofibroblast Differentiation for Attenuating Rheumatic Heart Disease Progression (RHD): An In Vitro Study

Abstract

Background: Chronic inflammation of RHD occurs and releasing proinflammatory cytokines, including Transforming Growth Factor β1 (TGF-β1) which induces myofibroblast differentiation. This differentiation plays crucial role on resulting fibrosis and calcification of the heart valve. This cascade of inflammation presents an opportunity for the use of antifibrotic agents such as angiotensin-converting enzyme (ACE) Inhibitor. However, no study provided an optimum dose nor comparison of various Lisinopril doses.

Methods: This study is an in vitro posttest-only control group study. Valvular Interstitial Cell (VIC) were obtained from New Zealand rabbit (Oryctolagus cuniculus) heart valves. Valve interstitial cells were divided into five groups of exposure TGF-β1 and various Lisinopril doses (1 µM, 10 µM, 100 µM). The effect of Lisinopril on myofibroblastic differentiation was evaluated by measuring αSMA expression using immunocytochemical methods. Statistical significance was determined using an independent T-test with a p-value < 0.05.

Results: The result of independent T test indicated a significantly lower αSMA expression in the group given Lisinopril at various doses compared to the group only induced by TGF-β1 (Lisinopril dose 1 µM, 10 µM, 100 µM; p<0.05). The lowest and most significant amount of αSMA expression was found in Lisinopril at a dose of 100 µM.

Conclusion: Lisinopril inhibited TGF-β1-induced myofibroblast development in rabbit valve interstitial cells at dosages of 1 µM, 10 µM, and 100 µM. The lowest fibrosis marker was observed with Lisinopril 100 µM.

1. Kumar RK, Antunes MJ, Beaton A, Mirabel M, Nkomo VT, Okello E, et al. Contemporary Diagnosis and Management of Rheumatic Heart Disease: Implications for Closing the Gap A Scientific Statement From the American Heart Association. Circulation. 2020;142(20):E337–57.
2. Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, Regional, and National Burden of Rheumatic Heart Disease, 1990–2015. New England Journal of Medicine. 2017;
3. Carapetis JR, Beaton A, Cunningham MW, Guilherme L, Karthikeyan G, Mayosi BM, et al. Acute rheumatic fever and rheumatic heart disease. Nature Reviews Disease Primers. 2016 Jan 14;2(1):15084.
4. Sika-Paotonu. Acute rheumatic fever and rheumatic heart disease. Nature Reviews Disease Primers. 2016 Jan 14;2(1):15085.
5. Kim L, Kim DK, Yang WI, Shin DH, Jung IM, Park HK, et al. Overexpression of Transforming Growth Factor-β1 in the Valvular Fibrosis of Chronic Rheumatic Heart Disease. Journal of Korean Medical Science. 2008;23(1):41.
6. Vaideeswar P, Butany J. Valvular Heart Disease. 4th ed. Cardiovascular Pathology: Fourth Edition. Elsevier Inc.; 2016. 485–528 p.
7. Hermawan HO, Ardiana M, Suryawan IGR, Harsoyo PM, Rafli M. Losartan Has a Comparable Effect to Human Recombinant ACE2 in Reducing Interleukin-6 (IL-6) Levels on Human Adipocytes Exposed to SARS-CoV-2 Spike Protein. The Indonesian Biomedical Journal [Internet]. 2023 Oct 18;15(5):311–7. Available from: https://inabj.org/index.php/ibj/article/view/2552
8. Oktaviono YH, Hutomo SA, Luke K. The Role of Endothelial Progenitor Cells in Coronary Artery Disease: Basic Molecular Mechanisms and Its Clinical Potentials. Indonesian Biomedical Journal. 2021;13(2):106–13.
9. Tan W, Fang Q, Shen XZ, Giani JF, Zhao T V, 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. British Journal of Pharmacology. 2018 Nov 8;175(22):4239–52.
10. Opie LH, Gersh BJ. Drugs for the Heart. 8th Editio. Drugs for the Heart: Expert Consult - Online and Print. Elsevier; 2013. 1–578 p.
11. Scisciola L, Fontanella RA, Surina, Garofalo G, Rizzo MR, Paolisso G, et al. Potential Role of Lisinopril in Reducing Atherosclerotic Risk: Evidence of an Antioxidant Effect in Human Cardiomyocytes Cell Line. Frontiers in Pharmacology. 2022 May 17;13.
12. Saxmose Nielsen S, Alvarez J, Bicout DJ, Calistri P, Depner K, Drewe JA, et al. Stunning methods and slaughter of rabbits for human consumption. EFSA Journal [Internet]. 2020 Jan 1 [cited 2023 Dec 10];18(1):e05927. Available from: https://onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2020.5927
13. Monzack EL, Gu X, Masters KS. Efficacy of Simvastatin Treatment of Valvular Interstitial Cells Varies With the Extracellular Environment. Arteriosclerosis, Thrombosis, and Vascular Biology. 2009 Feb;29(2):246–53.
14. Zhang Y, Lu Y, Ong’achwa MJ, Ge L, Qian Y, Chen L, et al. Resveratrol Inhibits the TGF- β 1-Induced Proliferation of Cardiac Fibroblasts and Collagen Secretion by Downregulating miR-17 in Rat. BioMed Research International. 2018 Dec 17;2018:1–10.
15. Eghbali M, Tomek R, Woods C, Bhambi B. Cardiac fibroblasts are predisposed to convert into myocyte phenotype: specific effect of transforming growth factor beta. Proceedings of the National Academy of Sciences. 1991 Feb;88(3):795–9.
16. Fang QQ, Wang XF, Zhao WY, Ding SL, Shi BH, Xia Y, et al. Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways. Scientific Reports. 2018 Feb 20;8(1):3332.
17. Suwanto D, Le A, Dharmadjati BB, Oktaviono YH, Subagjo A, Sativa O, et al. Inhibition of Pathological Myobroblast Differentiation of Valvular Interstitial Cell by Atorvastatin, Olmesartan, and Resveratrol in Experimental Heart Valve Model “Contemporary Model with Rabbit Valve.” 2022;(August):1–14.
18. Lijnen PJ, Petrov V V., Fagard RH. Induction of cardiac fibrosis by transforming growth factor-β1. Molecular Genetics and Metabolism. 2000;
19. Katwa LC, Campbell SE, Tyagi SC, Lee SJ, Cicila GT, Weber KT. Cultured Myofibroblasts Generate Angiotensin Peptidesde Novo. Journal of Molecular and Cellular Cardiology. 1997 May;29(5):1375–86.
Files
IssueArticles In Press QRcode
SectionOriginal Article(s)
Keywords
Lisinopril Rheumatic heart disease Valvular interstitial cell Myofibroblast Transforming Growth Factor β1
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Lefi A, Asmarani D, Dharmadjati B, Suwanto D, Saputra M, Pravitasari V, Anandita F. Efficacy of Optimal Dosage of Lisinopril in Inhibiting Myofibroblast Differentiation for Attenuating Rheumatic Heart Disease Progression (RHD): An In Vitro Study. J Tehran Heart Cent. 2024;.