Association of Heme Oxygenase-1 Promoter Polymorphisms and Plasma Heme Oxygenase-1 Levels with Atrial Septal Defect–Associated Pulmonary Arterial Hypertension
Article Sidebar
Views | PDF/EPUB Downloads:
0
/ 0
/ 0
Main Article Content
Abstract
Pulmonary arterial hypertension is a serious complication of atrial septal defect driven by oxidative stress and vascular remodelling. Heme oxygenase-1 (HO-1), encoded by the HMOX1 gene, exerts antioxidant and cytoprotective effects, and its expression is influenced by promoter polymorphisms. This study investigated the association of (GT)n repeats, rs2071746, and plasma HO-1 levels with atrial septal defect-pulmonary arterial hypertension (ASD-PAH) in the Javanese population. A total of 101 participants from Dr. Sardjito Hospital, Indonesia, were enrolled, including 51 ASD-PAH and 50 ASD patients non-PAH. Hemodynamic parameters were assessed by echocardiography and right heart catheterization. Plasma HO-1 and endothelin-1 levels were measured using ELISA. HMOX1 polymorphisms were analyzed using PCR-based methods, and associations were evaluated by logistic regression. ASD-PAH patients showed significantly higher pulmonary vascular resistance (8.15 ± 6.36 vs. 4.41 ± 6.72 Wood units; p = 0.0014), mean pulmonary arterial pressure (48.57 ± 16.67 vs. 37.55 ± 19.00 mmHg; p = 0.01), and endothelin-1 levels (p = 0.04). Plasma HO-1 levels did not differ significantly. The L allele of (GT)n repeats increased ASD-PAH risk (OR = 2.04; p = 0.015), while the rs2071746 T allele showed a strong association (OR = 4.61; p < 0.001), with AT+TT genotypes conferring >10-fold risk. Multivariate analysis confirmed that the S allele and higher HO-1 levels reduced ASD-PAH risk. HMOX1 polymorphisms and HO-1 expression influenced ASD-PAH susceptibility. The S allele and elevated HO-1 are protective, while the L and T alleles increase disease risk, supporting their potential as complementary biomarkers.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
How to Cite
References
1.Dinarti LK, Anggrahini DW, Hadwiono MR, Halim Wiradhika AM, Dewanto V, Hartopo AB. Pulmonary arterial hypertension after atrial septal defect closure: a case report. J Med Sci. 2021; 53(4).
2.Task A, Members F, Humbert M, Germany MMH, Berger RMF, Denmark JC, Germany EM, Germany, BN, Germany KMO, Kingdom JP, Quint JK, Kingdom U, France GS, France OS, Toshner M, Vachiery J, Noordegraaf A, Delcroix M, Rosenkranz S, . 2022 ESC / ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by the task force for the diagnosis and treatment of (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lu. Eur. Heart J. 2022;1–114.
3.Indonesian Association of Cardiovascular Specialists. Pulmonary Hypertension. 2021.
4.Shah AJ, Vorla M, Kalra DK. Molecular Pathways in Pulmonary Arterial Hypertension. Int J Mol Sci. 2022; 23(17).
5.Lau EMT, Tamura Y, McGoon MD, Sitbon O. The 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: A practical chronicle of progress. In: Eur. Res J. Eur. Res Soc.2015; 879–882.
6.Dinarti LK, Hartopo AB, Anggrahini DW, Sadewa AH, Setianto BY, Wahab AS. Profile of Endothelin-1, Nitric Oxide, and Prostacyclin Levels in Pulmonary Arterial Hypertension Related to Uncorrected Atrial Septal Defect: Results from a Single Center Study in Indonesia. Cardiol. Res Pract. 2020.
7.Dinarti LK, Hartopo AB, Kusuma AD, Satwiko MG, Hadwiono MR, Pradana AD, Anggrahini DW. The COngenital HeARt Disease in adult and Pulmonary Hypertension (COHARD-PH) registry: A descriptive study from single-center hospital registry of adult congenital heart disease and pulmonary hypertension in Indonesia. BMC Cardiovasc Disord. 2020; 20(1).
8.Bradley EA, Ammash N, Martinez SC, Chin K, Hebson C, Singh HS, Aboulhosn J, Grewal J, Billadello J, Chakinala MM, Daniels CJ, Zaidi A. “Treat-to-close”: Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry. Int. J Cardiol. 2019; 291: 127–133.
9.Prins KW, Thenappan T. World Health Organization Group I Pulmonary Hypertension: Epidemiology and Pathophysiology. Vol. 34, Cardiol Clin. W.B. Saunders; 2016; 363–374.
10.Del Pozo R, Hernandez Gonzalez I, Escribano-Subias P. The prostacyclin pathway in pulmonary arterial hypertension: a clinical review. Expert Rev Respir Med. 2017; 11(6): 491–503.
11.Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur. Res J. 2021; 58(3).
12.Nahar S, Kanda S, Chatha U, Odoma VA, Pitliya A, AlEdani EM, Bhangu J, Javed K, Manshahia P, Yu AK. Current Status of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension: A Combined Study Results and Pharmacology-Based Review. Cur. 2023.
13.Kishimoto Y, Ibe S, Saita E, Sasaki K, Niki H, Miura K, Ikegami Y, Ohmori R, Kondo K, Momiyama Y. Plasma Heme Oxygenase-1 Levels in Patients with Coronary and Peripheral Artery Diseases. Dis Markers. 2018: 1–9.
14.Ma LL, Sun L, Wang YX, Sun BH, Li YF, Jin YL. Association between HO-1 gene promoter polymorphisms and diseases (Review). Mol. Med. Rep. 2022; 25.
15.Durante W. Targeting heme oxygenase-1 in the arterial response to injury and disease. Antioxidants.2020; 9: 1–22.
16.Chen S Da, Wang XY, Nisar MF, Lin M, Zhong JL. Heme Oxygenases: Cellular Multifunctional and Protective Molecules against UV-Induced Oxidative Stress. Oxid Med Cell Longev.2019; 2019
17.Rusdiana R, Widjaja SS, Savira M, Amelia R, Rusmalawati R. Assessment of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Levels in Type 2 Diabetes Mellitus Patients in North Sumatera, Indonesia. Trop. J. Nat. Prod. Res. 2021; 5; 1919–1921.
18.Ryter SW. Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders. Antioxidants. 2022; 11
19.Duvigneau JC, Esterbauer H, Kozlov A V. Role of heme oxygenase as a modulator of heme-mediated pathways. Antioxidants. 2019; 8
20.van Loon RLE, Bartelds B, Wagener FADTG, Affara N, Mohaupt S, Wijnberg H, Pennings S, Takens J, Berger R. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase. Front Pediatr. 2015; 28(3).
21.Tanaka G, Aminuddin F, Akhabir L, He JQ, Shumansky K, Connett JE, Anthonisen N, Abboud RT, Paré P, Sandford A. Effect of heme oxygenase-1 polymorphisms on lung function and gene expression. BMC Med Genet. 2011; 8(12).
22.Chang PF, Lin YC, Liu K, Yeh SJ, Ni YH. Heme oxygenase-1 gene promoter polymorphism and the risk of pediatric nonalcoholic fatty liver disease. Int. J Obes. 2015; 39(8): 1236–1240.
23.Lv X, Li X, Dai X, Liu M, Wu C, Song W, Wang J, Ren X, Cai Y. Investigation heme oxygenase-1 polymorphism with the pathogenesis of preeclampsia. Clin. Exp. Hypertens. 2020; 42(2): 167–170.
24.Song P, Li K, Liu L, Wang X, Jian Z, Zhang W, Wang G, Li C, Gao T. Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations. J Cell Mol Med. 2016; 20(10):1840–1850.
25.Jain S, Dalvi B. Atrial septal defect with pulmonary hypertension: When/how can we consider closure? J Thorac Dis. 2018; 10: 2890–2898.
26.Supomo S, Widhinugroho A, Nugraha AA. Normalization of the right heart and the preoperative factors that influence the emergence PAH after surgical closure of atrial septal defect. J Cardiothorac Surg. 2020; 15(1):1–6.
27.Dara A, Arvanitaki A, Theodorakopoulou M, Athanasiou C, Pagkopoulou E, Boutou A. Non-Invasive Assessment of Endothelial Dysfunction in Pulmonary Arterial Hypertension. Mediterr. J Rheumatol. 2021; 32: 6–14.
28.Van Der Feen DE, Bartelds B, De Boer RA, Berger RMF. Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease. Heart. 2019; 105: 276–282.
29.Rubáčková Popelová J, Tomek J, Tomková M, Živná R. Normalization of Four Different Types of Pulmonary Hypertension After Atrial Septal Defect Closure. Front Cardiovasc Med. 2022; 9.
30.Anggrahini DW, Haidar S, Hartopo AB, Dinarti LK. Reversibility and outcome of fenestrated surgical closure in adult patients with congenital left-to-right shunts and pulmonary hypertension: a result of cohard-ph registry.2023.
31.Zolty R. Novel experimental therapies for treatment of pulmonary arterial hypertension. Vol. 13, J. exp. pharmacol. 2021; 817–857.
32.Santos-Gomes J, Gandra I, Adão R, Perros F, Brás-Silva C. An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers. Vol. 9, Front. cardiovasc. med.; 2022.
33.Ahn KJ, Jang AY, Park SJ, Chung WJ. 15 years journey of idiopathic pulmonary arterial hypertension with BMPR2 mutation. Clin Hypertens. 2019; 25(1):1–4.
34.Karita, Dewi ;Sadewa,Ahmad Hamim; Hastuti P. Original Article Association between polymorphism of lys198asn endothelin-1 gene and endothelin-1 plasma level in javanese obesity population. Bangladesh J. Med. Sci. 2019; 4(1):10–19.
35.Torres AJ. Hemodynamic assessment of atrial septal defects. J Thorac Dis; 2018; 10: 2882–2889.
36.Hariharan P, Chavan V, Nadkarni A. Significance of heme oxygenase-1(HMOX1) gene on fetal hemoglobin induction in sickle cell anemia patients. Sci Rep. 2020; 10(1).
37.Sun T, Cruz GI, Mousavi N, Marić I, Brewer A, Wong RJ, Aghaeepour N, Sayed N, Wu J, Stevenson D, Leonard S, Gymrek M, Winn V. HMOX1 Genetic Polymorphisms
Display Ancestral Diversity and May Be Linked to Hypertensive Disorders in Pregnancy. Repr. Sci. 2022; 29(12): 3465–3476.
38.Liang KW, Lee WJ, Lee WL, Wu JP, Lee I Te, Wang JS, Sheu, Wayne H.H. Subjects with coronary artery disease and reduced ejection fraction have longer (GT)n repeats in the heme-oxygenase 1 gene promoter. Heart Vessels. 2021; 36(5): 615–620.
39.Sandrim V, Coeli-Lacchini FB, Tanus-Santos JE, Lacchini R, Cavalli RC. Circulating HO-1 levels are not associated with plasma sFLT-1 and GT n HMOX1 polymorphism in preeclampsia. Hypertens Pregnancy. 2019; 38(2): 73–77.
40.Chiang SK, Chen SE, Chang LC. The role of HO-1 and its crosstalk with oxidative stress in cancer cell survival. Cells. 2021; 10
41.Hsu HH, Ko WJ, Hsu JY, Chen JS, Lee YC, Lai IR, Chen C. Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats. Respir Res. 2009; 10.
42.Zhang WH, Zhang YJ, Liu CP, Yu BX, Lu WX. Simvastatin protects against the development of monocrotaline-induced pulmonary hypertension in rats via a heme oxygenase-1dependent pathway. Exp Lung Res. 2011; 37(8): 492–499.
43.JEB S. CLARK 1 AJC 2, MD 2 and IA 2. Simvastatin Inhibits Epithelial-to-Mesenchymal Transition Through Induction of HO-1 in Cultured Renal Proximal Tubule Cells. In Vivo. 2016; 30:407–411.
44.Belhaj A, Dewachter L, Kerbaul F, Brimioulle S, Dewachter C, Naeije R, Rondelet, B. Heme Oxygenase-1 and Inflammation in Experimental Right Ventricular Failure on Prolonged Overcirculation-Induced Pulmonary Hypertension. PLoS One. 2013; 8(7).