ACE2 EXPRESSION OF HYPERTENSIVE RAT LUNGS GIVEN ACE-I, CCB, AND SWITCHING ACEI TO CCB

  • Muthiah Abustani Biomedical Science, Graduate student, Hasanuddin University
    (ID)

Abstract

Latar belakang : Hipertensi merupakan komorbid terbanyak pada COVID-19 dan ACE2 sebagai reseptor yang akan berikatan dengan virus SARS-COV-2, juga berperan dalam regulasi tekanan darah. Penggunaan obat antihipertensi seperti ACE-I atau CCB dapat mempengaruhi ekspresi ACE2. Penggunaan ACE-I selama pandemi menuai pro dan kontra yang memunculkan saran penggantian golongan obat antihipertensi seperti CCB. Tujuan : Mengetahui ekspresi ACE2 jaringan paru tikus setelah induksi hipertensi dan dilanjutkan dengan pemberian ACE-I (kaptopril) atau CCB (amlodipine), dan switching ACE-I menjadi CCB. Metode : Post control group design menggunakan 30 sampel tikus Sprague dawley yang dibagi menjadi 5 kelompok yaitu non-hipertensi, hipertensi, hipertensi + ACE-I, hipertensi + CCB, dan hipertensi + ACE-I switching CCB. Induksi hipertensi menggunakan L-NAME selama 6 minggu dan pengukuran tekanan darah menggunakan metode non-invasif. Pemberian obat antihipertensi diberikan selama 1 minggu. Ekspresi ACE2 diukur menggunakan ELISA kit Elabscience®. Hasil : Ekspresi ACE2 pada kelompok non hipertensi vs hipertensi tidak ditemukan perbedaan bermakna. Ekspresi ACE2 pada kelompok hipertensi dengan pengobatan ACE-I vs CCB ditemukan lebih tinggi pada kelompok CCB (p = 0.042). Ekspresi ACE2 pada kelompok hipertensi dengan pengobatan lebih tinggi dibanding kelompok hipertensi tanpa pengobatan (p = 0.001). Diskusi : Ekspresi ACE2 lebih tinggi pada kelompok dengan pengobatan ACE-I dengan cara menghambat efek Angiotensin II, sehingga kadar ACE2 meningkat sebagai mekanisme kompensasi. Sedangkan CCB akan meningkatkan kadar Angiotensin I dan menurunkan rasio Angiotensin (1-7)/ Angiotensin I dan menurunkan rasio ACE2/ACE Kesimpulan : Ekspresi ACE2 meningkat pada jaringan paru hipertensi dengan pengobatan ACE-I, CCB, dan switching ACE-I menjadi CCB.

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References

Aritomi, S. (2012). Cilnidipine, An L-/N-Type Calcium Channel Blocker, Changes the Circulating Angiotensin–(1-7)/Angiotensin II Ratio. Journal of Hypertension- Open Access, 01(01), 1–6. https://doi.org/10.4172/2167-1095.1000102

Babadaei, M. M. N., Hasan, A., Bloukh, S. H., Edis, Z., Sharifi, M., Kachooei, E., & Falahati, M. (2020). The expression level of angiotensin-converting enzyme 2 determines the severity of COVID-19: lung and heart tissue as targets. Journal of Biomolecular Structure and Dynamics, 0(0), 1–7. https://doi.org/10.1080/07391102.2020.1767211

Bai, S., Huang, Z. G., Chen, L., Wang, J. T., & Ding, B. P. (2013). Effects of felodipine combined with puerarin on ACE2-Ang (1-7)-Mas axis in renovascular hypertensive rat. Regulatory Peptides, 184, 54–61. https://doi.org/10.1016/j.regpep.2013.03.005

Bosso, M., Thanaraj, T. A., Abu-Farha, M., Alanbaei, M., Abubaker, J., & Al-Mulla, F. (2020). The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19. Molecular Therapy - Methods and Clinical Development, 18(September), 321–327. https://doi.org/10.1016/j.omtm.2020.06.017

Bulsara, Kishen G. ; Cassagnol, M. (2023). Amlodipine. Statpearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK519508/#:~:text=Peak plasma concentrations are achieved,approximately 40%25 to 60%25.

Burrell, L. M., Burchill, L., Dean, R. G., Griggs, K., Patel, S. K., & Velkoska, E. (2012). Chronic kidney disease: Cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition. Experimental Physiology, 97(4), 477–485. https://doi.org/10.1113/expphysiol.2011.063156

D’elia, J. A., & Weinrauch, L. A. (2018). Calcium ion channels: Roles in infection and sepsis mechanisms of calcium channel blocker benefits in immunocompromised patients at risk for infection. International Journal of Molecular Sciences, 19(9), 1–17. https://doi.org/10.3390/ijms19092465

Dambha-Miller, H., Albasri, A., Hodgson, S., Wilcox, C. R., Khan, S., Islam, N., Little, P., & Griffin, S. J. (2020). Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: A systematic review. BMJ Open, 10(9), 1–10. https://doi.org/10.1136/bmjopen-2020-040644

Diaz, J. H. (2021). Hypothesis: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. Journal of Travel Medicine, 27(3), 1–7. https://doi.org/10.1093/JTM/TAAA041

García-Escobar, A., Vera-Vera, S., Jurado-Román, A., Jiménez-Valero, S., Galeote, G., & Moreno, R. (2022). Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19. Biomolecules, 12(1), 1–17. https://doi.org/10.3390/biom12010076

Hamming, ME Cooper, BL Haagmans, NM Hooper, R Korstanje, ADME Osterhaus, W Timens, AJ Turner, G. N. and H. van G. (2007). The emerging role of ACE2 in physiology and disease. 1–11. https://doi.org/10.1002/path

Iizuka, K., Kusunoki, A., MacHida, T., & Hirafuji, M. (2009). Angiotensin II reduces membranous angiotensin-converting enzyme 2 in pressurized human aortic endothelial cells. JRAAS - Journal of the Renin-Angiotensin-Aldosterone System, 10(4), 210–215. https://doi.org/10.1177/1470320309343710

Jacobs, M., van Eeckhoutte, H. P., Wijnant, S. R. A., Janssens, W., Brusselle, G. G., Joos, G. F., & Bracke, K. R. (2020). Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects. European Respiratory Journal, 56(2). https://doi.org/10.1183/13993003.02378-2020

James, P. A., Oparil, S., Carter, B. L., Cushman, W. C., Dennison-Himmelfarb, C., Handler, J., Lackland, D. T., LeFevre, M. L., MacKenzie, T. D., Ogedegbe, O., Smith, S. C., Svetkey, L. P., Taler, S. J., Townsend, R. R., Wright, J. T., Narva, A. S., & Ortiz, E. (2014). 2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA - Journal of the American Medical Association, 311(5), 507–520. https://doi.org/10.1001/jama.2013.284427

Jia, H., Neptune, E., & Cui, H. (2021). Targeting ACE2 for COVID-19 Therapy: Opportunities and challenges. American Journal of Respiratory Cell and Molecular Biology, 64(4), 416–425. https://doi.org/10.1165/rcmb.2020-0322PS

Kemenkes RI. (2019). Hipertensi Si Pembunuh Senyap. Kementrian Kesehatan RI, 1–5. https://pusdatin.kemkes.go.id/resources/download/pusdatin/infodatin/infodatin-hipertensi-si-pembunuh-senyap.pdf

Kementerian Kesehatan, R. (2019). KEPUTUSAN MENTERI KESEHATAN REPUBLIK INDONESIA NOMOR HK.01.07/MENKES/813/2019 TENTANG FORMULARIUM NASIONAL. 8(5), 55.

Khan, S. H., & Zaidi, S. K. (2020). Review of evidence on using ACEi and ARBs in patients with hypertension and COVID-19. Drugs and Therapy Perspectives, 36(8), 347–350. https://doi.org/10.1007/s40267-020-00750-w

Khattak, Z., & Vlachadis Castles, A. (2021). Prescription of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blocking Agents in Australia During the COVID-19 Pandemic. Heart, Lung and Circulation, 30, S113–S114. https://doi.org/10.1016/j.hlc.2021.06.048

Kim, H. J., Han, S. J., Kim, D. J., Jang, H. C., Lim, S., Choi, S. H., Kim, Y. H., Shin, D. H., Kim, S. H., Kim, T. H., Ahn, Y. B., Ko, S. H., Kim, N. H., Seo, J. A., Kim, H. Y., & Lee, K. W. (2017). Effects of valsartan and amlodipine on oxidative stress in type 2 diabetic patients with hypertension: A randomized, multicenter study. Korean Journal of Internal Medicine, 32(3), 497–504. https://doi.org/10.3904/kjim.2015.404

Kuster, G. M., & Osswald, S. (2020). Switching antihypertensive therapy in times of COVID-19: Why we should wait for the evidence. European Heart Journal, 41(19), 1857. https://doi.org/10.1093/eurheartj/ehaa335

Lebek, S., Tafelmeier, M., Messmann, R., Provaznik, Z., Schmid, C., Maier, L. S., Birner, C., Arzt, M., & Wagner, S. (2020). Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease. European Journal of Heart Failure, 22(12), 2248–2257. https://doi.org/10.1002/ejhf.2020

Li, Y., Zeng, Z., Li, Y., Huang, W., Zhou, M., Zhang, X., & Jiang, W. (2015). ANGIOTENSIN-CONVERTING ENZYME INHIBITION ATTENUATES LIPOPOLYSACCHARIDE-INDUCED LUNG INJURY BY REGULATING THE BALANCE BETWEEN ANGIOTENSIN-CONVERTING ENZYME AND ANGIOTENSIN-CONVERTING ENZYME 2 AND INHIBITING MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION. 43(4). https://doi.org/10.1097/SHK.0000000000000302

Mills, K. T., Stefanescu, A., & He, J. (2020). The global epidemiology of hypertension. Nature Reviews Nephrology, 16(4), 223–237. https://doi.org/10.1038/s41581-019-0244-2

Mizuiri, S. (2015). ACE and ACE2 in kidney disease. World Journal of Nephrology, 4(1), 74. https://doi.org/10.5527/wjn.v4.i1.74

Pechanova, O., Vrankova, S., & Cebova, M. (2020). Chronic L-Name-Treatment Produces Hypertension by Di ff erent Mechanisms in Peripheral Tissues and Brain : Role of Central eNOS. 46–54.

Pranata, R., Lim, M. A., Huang, I., Raharjo, S. B., & Lukito, A. A. (2020). Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: A systematic review, meta-analysis and meta-regression. JRAAS - Journal of the Renin-Angiotensin-Aldosterone System, 21(2). https://doi.org/10.1177/1470320320926899

Prof. Giovanni de Simone. (2020). Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. In European Society of Cardiology (pp. 1–1).

Pubmed. (2022). Index @ Pubmed.Ncbi.Nlm.Nih.Gov. National Library of Medicine. https://pubmed.ncbi.nlm.nih.gov/?term=ace2&filter=years.1981-2004&timeline=expanded

Rysz, J., Franczyk, B., Rysz-Górzyńska, M., & Gluba-Brzózka, A. (2020). Pharmacogenomics of hypertension treatment. International Journal of Molecular Sciences, 21(13), 1–26. https://doi.org/10.3390/ijms21134709

Saheb Sharif-Askari, N., Saheb Sharif-Askari, F., Alabed, M., Tayoun, A. A., Loney, T., Uddin, M., Senok, A., Al Heialy, S., Hamoudi, R., Kashour, T., Alsheikh-Ali, A., Hamid, Q., & Halwani, R. (2020). Effect of Common Medications on the Expression of SARS-CoV-2 Entry Receptors in Kidney Tissue. Clinical and Translational Science, 13(6), 1048–1054. https://doi.org/10.1111/cts.12862

Semenzato, L., Botton, J., Drouin, J., Baricault, B., Vabre, C., Cuenot, F., Penso, L., Herlemont, P., Sbidian, E., Weill, A., Dray-Spira, R., & Zureik, M. (2021). Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients. Hypertension, 77(3), 833–842. https://doi.org/10.1161/HYPERTENSIONAHA.120.16314

Silva, I. V. G., De Figueiredo, R. C., & Rios, D. R. A. (2019). Effect of different classes of antihypertensive drugs on endothelial function and inflammation. International Journal of Molecular Sciences, 20(14), 5–9. https://doi.org/10.3390/ijms20143458

Sinha, S., Cheng, K., Schäffer, A. A., Aldape, K., Schiff, E., & Ruppin, E. (2020). In vitro and in vivo identification of clinically approved drugs that modify ACE 2 expression . Molecular Systems Biology, 16(7), 1–9. https://doi.org/10.15252/msb.20209628

Soria-castro, E., Ibarra-lara, L., Valle-mondrago, L. Del, Pe, F., Torres-narva, J. C., Cervantes-pe, L. G., Pastelı, G. S., & Ramı, M. (2016). Peroxisome proliferator-activated receptor- a stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle. 68, 692–702. https://doi.org/10.1016/j.pharep.2016.03.002

Trifirò, G., Crisafulli, S., Andò, G., Racagni, G., Drago, F., Berrino, L., Re, M., Bernardini, R., Chiamulera, C., D’Avolio, A., Pani, L., Clementi, E., Capuano, A., Scaglione, F., Danesi, R., Cirino, G., Mugelli, A., Bonanno, G., Brunello, N., … Taglialatela, M. (2020). Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)? Drug Safety, 43(6), 507–509. https://doi.org/10.1007/s40264-020-00935-2

Whelton, P. K., Carey, R. M., Aronow, W. S., Casey, D. E., Collins, K. J., Himmelfarb, C. D., DePalma, S. M., Gidding, S., Jamerson, K. A., Jones, D. W., MacLaughlin, E. J., Muntner, P., Ovbiagele, B., Smith, S. C., Spencer, C. C., Stafford, R. S., Taler, S. J., Thomas, R. J., Williams, K. A., … Wright, J. T. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American college of cardiology/American Heart Association task . In Hypertension (Vol. 71, Issue 6). https://doi.org/10.1161/HYP.0000000000000066

WHO. (2020). COVID-19 and the use of angiotensin-converting enzyme inhibitors and receptor blockers. Scientific brief. Scientific Brief, 16(1), 120–121. https://doi.org/10.15557/PiMR.2020.0023

WHO. (2021). Hypertension. World Health Organization. https://www.who.int/health-topics/hypertension#tab=tab_1

Wysocki, J., Lores, E., Ye, M., Soler, M. J., & Batlle, D. (2020). Kidney and Lung ACE2 Expression after an ACE Inhibitor or an Ang II Receptor Blocker: Implications for COVID-19. Journal of the American Society of Nephrology, 31(9), 1941–1943. https://doi.org/10.1681/ASN.2020050667

Xiong, Q., Cao, L., Ma, C., Tortorici, M. A., Liu, C., Si, J., Liu, P., Gu, M., Walls, A. C., Wang, C., Shi, L., Tong, F., Huang, M., Li, J., Zhao, C., Shen, C., Chen, Y., Zhao, H., Lan, K., … Yan, H. (2022). Close relatives of MERS-CoV in bats use ACE2 as their functional receptors. Nature, 612(7941), 748–757. https://doi.org/10.1038/s41586-022-05513-3

Xudong, X., Junzhu, C., Xingxiang, W., Furong, Z., & Yanrong, L. (2006). Age- and gender-related difference of ACE2 expression in rat lung. Life Sciences, 78(19), 2166–2171. https://doi.org/https://doi.org/10.1016/j.lfs.2005.09.038

Yang, J., Petitjean, S. J. L., Koehler, M., Zhang, Q., Dumitru, A. C., Chen, W., Derclaye, S., Vincent, S. P., Soumillion, P., & Alsteens, D. (2020). Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-18319-6

Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., & Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet, 395(10229), 1054–1062. https://doi.org/10.1016/S0140-6736(20)30566-3

Published
2025-01-02
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