{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:53:25Z","timestamp":1791665605356,"version":"4.3.4"},"reference-count":62,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg\/kg) was administered to rats with PAH (monocrotaline 60 mg\/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 \u00b1 0.01 vs. 0.47 \u00b1 0.06 pmoles\/mL, allicin and control, respectively) and plasma (0.57 \u00b1 0.05 vs. 0.75 \u00b1 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 \u00b1 1.22 and 51.4 \u00b1 3.45 pmoles\/mL), tetrahydrobiopterin (8.43 \u00b1 0.33 and 10.14 \u00b1 0.70 pmoles\/mL), cyclic guanosine monophosphate (5.54 \u00b1 0.42 and 5.64 \u00b1 0.73 pmoles\/mL), and Ang-(1-7) (0.88 \u00b1 0.23 and 0.83 \u00b1 0.056 pmoles\/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 \u00b1 0.3 and 5.64 \u00b1 0.73 pmoles\/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1\u03b1 and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1\u03b1 and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.<\/jats:p>","DOI":"10.3390\/ijms241612959","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:33:11Z","timestamp":1692581591000},"page":"12959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Allicin, an Emerging Treatment for Pulmonary Arterial Hypertension: An Experimental Study"],"prefix":"10.3390","volume":"24","author":[{"given":"Jos\u00e9 L.","family":"S\u00e1nchez-Gloria","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5128-7695","authenticated-orcid":false,"given":"Constanza E.","family":"Mart\u00ednez-Olivares","sequence":"additional","affiliation":[{"name":"Experimental Pathology Department, Experimental Pathology Laboratory, Instituto Nacional de Ciencia M\u00e9dicas y Nutrici\u00f3n \u201cSalvador Zubir\u00e1n\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Del Valle-Mondrag\u00f3n","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda \u201cDr. Rafael M\u00e9ndez Mart\u00ednez\u201d, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6697-546X","authenticated-orcid":false,"given":"Fernando","family":"Cort\u00e9s-Camacho","sequence":"additional","affiliation":[{"name":"Departamento de Fisiopatolog\u00eda Cardio-Renal, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar R.","family":"Zambrano-V\u00e1squez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiopatolog\u00eda Cardio-Renal, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1292-3833","authenticated-orcid":false,"given":"Rogelio","family":"Hern\u00e1ndez-Pando","sequence":"additional","affiliation":[{"name":"Experimental Pathology Department, Experimental Pathology Laboratory, Instituto Nacional de Ciencia M\u00e9dicas y Nutrici\u00f3n \u201cSalvador Zubir\u00e1n\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6556-1632","authenticated-orcid":false,"given":"Fausto","family":"S\u00e1nchez-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Departamento de Inmunolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura G.","family":"S\u00e1nchez-Lozada","sequence":"additional","affiliation":[{"name":"Departamento de Fisiopatolog\u00eda Cardio-Renal, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9238-4202","authenticated-orcid":false,"given":"Horacio","family":"Osorio-Alonso","sequence":"additional","affiliation":[{"name":"Departamento de Fisiopatolog\u00eda Cardio-Renal, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12020","DOI":"10.1002\/pul2.12020","article-title":"Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study","volume":"12","author":"Johnson","year":"2022","journal-title":"Pulm. Circ."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Gloria, J.L., Arellano-Buend\u00eda, A.S., Ju\u00e1rez-Rojas, J.G., Garc\u00eda-Arroyo, F.E., Arg\u00fcello-Garc\u00eda, R., S\u00e1nchez-Mu\u00f1oz, F., S\u00e1nchez-Lozada, L.G., and Osorio-Alonso, H. (2022). Cellular Mechanisms Underlying the Cardioprotective Role of Allicin on Cardiovascular Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169082"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1001\/jama.2022.4402","article-title":"Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review","volume":"327","author":"Ruopp","year":"2022","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ruaro, B., Salton, F., Baratella, E., Confalonieri, P., Geri, P., Pozzan, R., Torregiani, C., Bulla, R., Confalonieri, M., and Matucci-Cerinic, M. (2022). An Overview of Different Techniques for Improving the Treatment of Pulmonary Hypertension Secondary in Systemic Sclerosis Patients. Diagnostics, 12.","DOI":"10.3390\/diagnostics12030616"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ejphar.2014.07.026","article-title":"Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats","volume":"740","author":"Ahmed","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Gloria, J.L., Mart\u00ednez-Olivares, C.E., Rojas-Morales, P., Hern\u00e1ndez-Pando, R., Carb\u00f3, R., Rubio-Gayosso, I., Arellano-Buend\u00eda, A.S., Rada, K.M., S\u00e1nchez-Mu\u00f1oz, F., and Osorio-Alonso, H. (2021). Anti-Inflammatory Effect of Allicin Associated with Fibrosis in Pulmonary Arterial Hypertension. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168600"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ahj.2022.12.009","article-title":"Pursuing functional biomarkers in complex disease: Focus on pulmonary arterial hypertension","volume":"258","author":"Benincasa","year":"2023","journal-title":"Am. Hear. J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Novoyatleva, T. (2023). Pulmonary Hypertension: New Insights and Recent Advances from Basic Science to Translational Approaches. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108462"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1161\/ATVBAHA.118.312262","article-title":"Epigenetic Inheritance Underlying Pulmonary Arterial Hypertension","volume":"39","author":"Napoli","year":"2019","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s12265-022-10294-1","article-title":"Association Between Circulating CD4+ T Cell Methylation Signatures of Network-Oriented SOCS3 Gene and Hemodynamics in Patients Suffering Pulmonary Arterial Hypertension","volume":"16","author":"Benincasa","year":"2022","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, H., Laux, A., Stenmark, K.R., and Hu, C.-J. (2021). Mechanisms Contributing to the Dysregulation of miRNA-124 in Pulmonary Hypertension. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083852"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH715>3.0.CO;2-Q","article-title":"Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension","volume":"192","author":"Orte","year":"2000","journal-title":"J. Pathol."},{"key":"ref_13","first-page":"305","article-title":"Recent Progress in Signal Transduction Research of the Angiotensin II Type-1 Receptor: Protein Kinases, Vascular Dysfunction and Structural Requirement","volume":"3","author":"Suzuki","year":"2005","journal-title":"Curr. Med. Chem. Hematol. Agents"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1164\/rccm.201203-0411OC","article-title":"Dysregulated Renin\u2013Angiotensin\u2013Aldosterone System Contributes to Pulmonary Arterial Hypertension","volume":"186","author":"Tu","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1902416","DOI":"10.1183\/13993003.02416-2019","article-title":"Angiotensin converting enzyme 2 and angiotensin (1\u20137) axis in pulmonary arterial hypertension","volume":"56","author":"Sandoval","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1161\/01.RES.82.12.1298","article-title":"Superoxide Production in Vascular Smooth Muscle Contributes to Oxidative Stress and Impaired Relaxation in Atherosclerosis","volume":"82","author":"Miller","year":"1998","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1089\/ars.2012.4641","article-title":"Angiotensin II, NADPH oxidase, and redox signaling in the vasculature","volume":"19","author":"Montezano","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1093\/cvr\/cvu061","article-title":"Smooth muscle cell-specific Hif-1\u03b1 deficiency suppresses angiotensin II-induced vascular remodelling in mice","volume":"102","author":"Imanishi","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"H736","DOI":"10.1152\/ajpheart.00937.2006","article-title":"Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1\u20137)","volume":"292","author":"Grobe","year":"2007","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1164\/rccm.200912-1840OC","article-title":"The angiotensin-converting enzyme 2\/angiogenesis-(1-7)\/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension","volume":"182","author":"Shenoy","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S1767","DOI":"10.21037\/jtd.2019.09.14","article-title":"Pharmacotherapy for pulmonary arterial hypertension","volume":"11","author":"Parikh","year":"2019","journal-title":"J. Thorac. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Trejo, E.M.G., Buend\u00eda, A.S.A., Reyes, O.S., Arroyo, F.E.G., Garc\u00eda, R.A., Mendoza, M.L.L., Tapia, E., Lozada, L.G.S., and Alonso, H.O. (2017). The Beneficial Effects of Allicin in Chronic Kidney Disease Are Comparable to Losartan. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091980"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3850402","DOI":"10.1155\/2016\/3850402","article-title":"Effects of Allicin on Hypertension and Cardiac Function in Chronic Kidney Disease","volume":"2016","author":"Tapia","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_24","first-page":"170","article-title":"Effects of allicin on cardiovascular risk factors in spontaneously hypertensive rats","volume":"15","author":"Elkayam","year":"2013","journal-title":"Isr. Med. Assoc. J. IMAJ"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H2431","DOI":"10.1152\/ajpheart.00384.2006","article-title":"Allicin in garlic protects against coronary endothelial dysfunction and right heart hypertrophy in pulmonary hypertensive rats","volume":"291","author":"Sun","year":"2006","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.lwt.2014.01.044","article-title":"Preparation and physicochemical characteristics of an allicin nanoliposome and its release behavior","volume":"57","author":"Lu","year":"2014","journal-title":"LWT-Food Sci. Technol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Gloria, J.L., Osorio-Alonso, H., Arellano-Buend\u00eda, A.S., Carb\u00f3, R., Hern\u00e1ndez-D\u00edazcouder, A., Guzm\u00e1n-Mart\u00edn, C.A., Rubio-Gayosso, I., and S\u00e1nchez-Mu\u00f1oz, F. (2020). Nutraceuticals in the Treatment of Pulmonary Arterial Hypertension. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144827"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"232","DOI":"10.5530\/pj.2020.12.35","article-title":"High Dose Allicin with Vitamin C Improves EPCs Migration from the Patient with Coronary Artery Disease","volume":"12","author":"Oktaviono","year":"2020","journal-title":"Pharmacogn. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1139\/cjpp-2015-0267","article-title":"Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin","volume":"94","author":"Ghoneim","year":"2016","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pupt.2015.09.007","article-title":"Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach","volume":"35","author":"Vitorino","year":"2015","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1164\/rccm.201710-2079OC","article-title":"Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2\u03b1 Inhibitor","volume":"198","author":"Dai","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/978-1-4939-8597-5_18","article-title":"Pulmonary Artery Hypertension Model in Rats by Monocrotaline Administration","volume":"1816","author":"Sassi","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coph.2017.12.002","article-title":"Targeting the renin\u2013angiotensin system as novel therapeutic strategy for pulmonary diseases","volume":"40","author":"Tan","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1159\/000346884","article-title":"The Changes of Serum Angiotensin-Converting Enzyme 2 in Patients with Pulmonary Arterial Hypertension due to Congenital Heart Disease","volume":"124","author":"Dai","year":"2013","journal-title":"Cardiology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-0115(99)00027-0","article-title":"Angiotensin II and nitric oxide: A question of balance","volume":"81","author":"Millatt","year":"1999","journal-title":"Regul. Pept."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/j.1476-5381.2012.01827.x","article-title":"Endothelial actions of atrial and B-type natriuretic peptides","volume":"166","author":"Kuhn","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.59249\/NCST6937","article-title":"Natriuretic Peptides as Biomarkers: Narrative Review and Considerations in Cardiovascular and Respiratory Dysfunctions","volume":"96","author":"Samad","year":"2023","journal-title":"Yale J. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1089\/ars.2012.4568","article-title":"Reactive Oxygen Species and Antioxidants in Pulmonary Hypertension","volume":"18","author":"Wong","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1161\/HYPERTENSIONAHA.113.02360","article-title":"Oxidative stress is associated with increased pulmonary artery systolic pressure in humans","volume":"63","author":"Ghasemzadeh","year":"2014","journal-title":"Hypertension"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1161\/01.HYP.0000254415.31362.a7","article-title":"Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling","volume":"49","author":"Takimoto","year":"2007","journal-title":"Hypertension"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/j.1582-4934.2004.tb00270.x","article-title":"Redox regulation of angiotensin II signaling in the heart","volume":"8","author":"Das","year":"2004","journal-title":"J. Cell Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.pharmthera.2008.05.010","article-title":"Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks","volume":"119","author":"Wenzel","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1097\/00004872-200202000-00018","article-title":"Irbesartan lowers superoxide levels and increases nitric oxide bioavailability in blood vessels from spontaneously hypertensive stroke-prone rats","volume":"20","author":"Brosnan","year":"2002","journal-title":"J. Hypertens."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1161\/01.CIR.94.3.258","article-title":"Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study","volume":"94","author":"Mancini","year":"1996","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s10557-012-6415-z","article-title":"Allicin Ameliorates Cardiac Hypertrophy and Fibrosis through Enhancing of Nrf2 Antioxidant Signaling Pathways","volume":"26","author":"Li","year":"2012","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3317\/jraas.2003.003","article-title":"Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: Increased frequency and association with preserved haemodynamics","volume":"4","author":"Abraham","year":"2003","journal-title":"J. Renin-Angiotensin-Aldosterone Syst."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"584758","DOI":"10.1155\/2015\/584758","article-title":"Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway?","volume":"2015","author":"Kumar","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev-physiol-021113-170322","article-title":"Hypoxia-Inducible Factor 1 and Cardiovascular Disease","volume":"76","author":"Semenza","year":"2014","journal-title":"Annu. Rev. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.3892\/etm.2021.10599","article-title":"Angiotensin-converting enzyme 2 alleviates pulmonary artery hypertension through inhibition of focal adhesion kinase expression","volume":"22","author":"Wang","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H995","DOI":"10.1152\/ajpheart.00562.2010","article-title":"Tumor necrosis factor inhibitors as novel therapeutic tools for vascular remodeling diseases","volume":"299","author":"Lambert","year":"2010","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1210\/en.2007-0285","article-title":"Differential Regulation of Hypoxia-Inducible Factor-1 through Receptor Tyrosine Kinase Transactivation in Vascular Smooth Muscle Cells","volume":"148","author":"Lauzier","year":"2007","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Leopold, J.A., and Maron, B.A. (2016). Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050761"},{"key":"ref_53","first-page":"197","article-title":"T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis","volume":"20","author":"Boleto","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.drudis.2022.01.011","article-title":"An emerging strategy for targeted therapy of pulmonary arterial hypertension: Vasodilation plus vascular remodeling inhibition","volume":"27","author":"Hu","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.jnutbio.2009.11.001","article-title":"Allicin protects against cardiac hypertrophy and fibrosis via attenuating reactive oxygen species-dependent signaling pathways","volume":"21","author":"Liu","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e00184","DOI":"10.1002\/phy2.184","article-title":"Progressive right ventricular functional and structural changes in a mouse model of pulmonary arterial hypertension","volume":"1","author":"Wang","year":"2013","journal-title":"Physiol. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2045894019841987","article-title":"Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension","volume":"9","author":"Zhu","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_58","first-page":"e53335","article-title":"Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension","volume":"11","author":"Ma","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"120091","DOI":"10.1016\/j.lfs.2021.120091","article-title":"Cold exposure aggravates pulmonary arterial hypertension through increased miR-146a-5p, miR-155-5p and cytokines TNF-\u03b1, IL-1\u03b2, and IL-6","volume":"287","author":"Sandoval","year":"2021","journal-title":"Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1164\/rccm.201402-0322OC","article-title":"Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor\/CD74 Complex","volume":"192","author":"Tu","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"8531975","DOI":"10.1155\/2021\/8531975","article-title":"Role of the Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the Regulation of Nitric Oxide Release in Wistar Rat Aorta","volume":"2021","author":"Arenas","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1016\/j.talanta.2009.10.010","article-title":"Simultaneous determination of angiotensins II and 1-7 by capillary zone electrophoresis in plasma and urine from hypertensive rats","volume":"80","year":"2010","journal-title":"Talanta"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:37:25Z","timestamp":1760128645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,19]]},"references-count":62,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612959"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612959","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,19]]}}}