Adrenomedullin improved endothelial dysfunction via receptor-Akt pathway in rats with obesity-related hypertension.
Adrenomedullin
Endothelial dysfunction
Inflammation
Obesity-related hypertension
Oxidative stress
Journal
Hypertension research : official journal of the Japanese Society of Hypertension
ISSN: 1348-4214
Titre abrégé: Hypertens Res
Pays: England
ID NLM: 9307690
Informations de publication
Date de publication:
21 May 2024
21 May 2024
Historique:
received:
04
08
2023
accepted:
07
04
2024
revised:
28
01
2024
medline:
21
5
2024
pubmed:
21
5
2024
entrez:
20
5
2024
Statut:
aheadofprint
Résumé
Obesity-related hypertension (OH) is accompanied by obvious endothelial dysfunction, which contributes to increased peripheral vascular resistance and hypertension. Adrenomedullin (ADM), a multifunctional active peptide, is elevated in obese humans. The OH rats induced by high fat diet (HFD) for 28 weeks and the human umbilical vein endothelial cells (HUVECs)-treated by palmitic acid (PA) were used to investigate the effects of ADM on endothelial dysfunction and the underlying mechanisms. Vascular reactivity was assessed using mesenteric arteriole rings, and the protein expression levels were examined by Western blot analysis. Compared with the control rats, OH rats exhibited hypertension and endothelial dysfunction, along with reduced eNOS protein expression and Akt activation, and increased protein expression of proinflammatory cytokines and ROS levels. Four-week ADM administration improved hypertension and endothelial function, increased eNOS protein expression and Akt activation, and attenuated endothelial inflammation and oxidative stress in OH rats. In vitro experiment, the antagonism of ADM receptors with ADM22-52 and the suppression of Akt signaling with A6730 significantly blocked ADM-caused increase of NO content and activation of eNOS and Akt, and inhibited the anti-inflammatory and anti-oxidant effect of ADM in PA-stimulated HUVECs. These data indicate that endothelial dysfunction in OH rats is partially attributable to the decreased NO level, and the increased inflammation and oxidative stress. ADM improves endothelial function and exerts hypotensive effect depending on the increase of NO, and its anti-inflammatory and anti-oxidant effect via receptor-Akt pathway.
Identifiants
pubmed: 38769138
doi: 10.1038/s41440-024-01701-y
pii: 10.1038/s41440-024-01701-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.
Références
Lin X, Li H. Obesity: Epidemiology, Pathophysiology, and Therapeutics. Front Endocrinol (Lausanne). 2021;12:706978.
pubmed: 34552557
doi: 10.3389/fendo.2021.706978
Piche ME, Tchernof A, Despres JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res. 2020;126:1477–1500.
pubmed: 32437302
doi: 10.1161/CIRCRESAHA.120.316101
Seravalle G, Grassi G. Obesity and hypertension. Pharm Res. 2017;122:1–7.
doi: 10.1016/j.phrs.2017.05.013
Silveira Rossi JL, Barbalho SM, Reverete de Araujo R, Bechara MD, Sloan KP, Sloan LA. Metabolic syndrome and cardiovascular diseases: Going beyond traditional risk factors. Diabetes Metab Res Rev. 2022;38:e3502.
pubmed: 34614543
doi: 10.1002/dmrr.3502
Virdis A, Neves MF, Duranti E, Bernini G, Taddei S. Microvascular endothelial dysfunction in obesity and hypertension. Curr Pharm Des. 2013;19:2382–9.
pubmed: 23173587
doi: 10.2174/1381612811319130006
Gallo G, Volpe M, Savoia C. Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications. Front Med (Lausanne). 2021;8:798958.
pubmed: 35127755
doi: 10.3389/fmed.2021.798958
Gao J, Pan X, Li G, Chatterjee E, Xiao J. Physical Exercise Protects Against Endothelial Dysfunction in Cardiovascular and Metabolic Diseases. J Cardiovasc Transl Res. 2022;15:604–20.
pubmed: 34533746
doi: 10.1007/s12265-021-10171-3
Jebari-Benslaiman S, Galicia-Garcia U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, et al. Pathophysiology of Atherosclerosis. Int J Mol Sci. 2022;23:3346.
pubmed: 35328769
pmcid: 8954705
doi: 10.3390/ijms23063346
Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric Oxide and Endothelial Dysfunction. Crit Care Clin. 2020;36:307–21.
pubmed: 32172815
pmcid: 9015729
doi: 10.1016/j.ccc.2019.12.009
Mallick R, Duttaroy AK. Modulation of endothelium function by fatty acids. Mol Cell Biochem. 2022;477:15–38.
pubmed: 34529222
doi: 10.1007/s11010-021-04260-9
Rana MN, Neeland IJ. Adipose Tissue Inflammation and Cardiovascular Disease: An Update. Curr Diab Rep. 2022;22:27–37.
pubmed: 35179694
doi: 10.1007/s11892-021-01446-9
Engin A. Endothelial Dysfunction in Obesity. Adv Exp Med Biol. 2017;960:345–79.
pubmed: 28585207
doi: 10.1007/978-3-319-48382-5_15
Marziano C, Genet G, Hirschi KK. Vascular endothelial cell specification in health and disease. Angiogenesis. 2021;24:213–36.
pubmed: 33844116
pmcid: 8205897
doi: 10.1007/s10456-021-09785-7
Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011;12:3117–32.
pubmed: 21686173
pmcid: 3116179
doi: 10.3390/ijms12053117
Iantorno, M; Campia, U; Di Daniele, N; Nistico, S; Forleo, GB; Cardillo, C; et al. Obesity, inflammation and endothelial dysfunction. (0393-974X (Print)).
Chrysant SG. Pathophysiology and treatment of obesity-related hypertension. J Clin Hypertens (Greenwich). 2019;21:555–9.
pubmed: 30907058
doi: 10.1111/jch.13518
Cohen JB, Gadde KM. Weight Loss Medications in the Treatment of Obesity and Hypertension. Curr Hypertens Rep. 2019;21:16.
pubmed: 30747357
pmcid: 6415530
doi: 10.1007/s11906-019-0915-1
Cheung BM, Tang F. Adrenomedullin: exciting new horizons. Recent Pat Endocr Metab Immune Drug Discov. 2012;6:4–17.
pubmed: 22216776
doi: 10.2174/187221412799015263
Hay DL, Garelja ML, Poyner DR, Walker CS. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharm. 2018;175:3–17.
doi: 10.1111/bph.14075
Kato J, Kitamura K. Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharm. 2015;764:140–8.
doi: 10.1016/j.ejphar.2015.06.061
Metwalley KA, Farghaly HS, Sherief T. Plasma adrenomedullin level in children with obesity: relationship to left ventricular function. World J Pediatr. 2018;14:84–91.
pubmed: 29411326
doi: 10.1007/s12519-017-0106-6
Nomura I, Kato J, Tokashiki M, Kitamura K. Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity. Regul Pept. 2009;158:127–31.
pubmed: 19706311
doi: 10.1016/j.regpep.2009.08.003
Theuerle J, Farouque O, Vasanthakumar S, Patel SK, Burrell LM, Clark DJ, et al. Plasma endothelin-1 and adrenomedullin are associated with coronary artery function and cardiovascular outcomes in humans. Int J Cardiol. 2019;291:168–72.
pubmed: 30987836
doi: 10.1016/j.ijcard.2019.04.008
Hosomi N, Ohyama H, Takahashi T, Shinomiya K, Naya T, Ban CR, et al. Plasma adrenomedullin and carotid atherosclerosis in atherothrombotic ischemic stroke. J Hypertens. 2004;22:1945–51.
pubmed: 15361766
doi: 10.1097/00004872-200410000-00017
Yuyun MF, Narayan HK, Quinn PA, Struck J, Bergmann A, Hartmann O, et al. Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction. J Cardiovasc Med (Hagerstown). 2017;18:42–50.
pubmed: 26766169
doi: 10.2459/JCM.0000000000000299
Voors AA, Kremer D, Geven C, Ter Maaten JM, Struck J, Bergmann A, et al. Adrenomedullin in heart failure: pathophysiology and therapeutic application. Eur J Heart Fail. 2019;21:163–71.
pubmed: 30592365
doi: 10.1002/ejhf.1366
Yuan M, Wang Q, Li C, Tao L, Zhang H, Wang H, et al. Adrenomedullin in Vascular Endothelial Injury and Combination Therapy: Time for a New Paradigm. Curr Vasc Pharm. 2015;13:459–66.
doi: 10.2174/1570161112666141014145735
Murakami S, Kimura H, Kangawa K, Nagaya N, Physiological significance and therapeutic potential of adrenomedullin in pulmonary hypertension. (1871-529X (Print)).
Makino I, Shibata K, Makino Y, Kangawa K, Kawarabayashi T. Adrenomedullin attenuates the hypertension in hypertensive pregnant rats induced by N(G)-nitro-L-arginine methyl ester. Eur J Pharm. 1999;371:159–67.
doi: 10.1016/S0014-2999(99)00151-X
Geven C, Bergmann A, Kox M, Pickkers P. Vascular Effects of Adrenomedullin and the Anti-Adrenomedullin Antibody Adrecizumab in Sepsis. Shock. 2018;50:132–40.
pubmed: 29324626
doi: 10.1097/SHK.0000000000001103
Yanagawa B, Nagaya N. Adrenomedullin: molecular mechanisms and its role in cardiac disease. Amino Acids. 2007;32:157–64.
pubmed: 16583314
doi: 10.1007/s00726-005-0279-5
Hamid SA, Baxter GF. A critical cytoprotective role of endogenous adrenomedullin in acute myocardial infarction. J Mol Cell Cardiol. 2006;41:360–3.
pubmed: 16842816
doi: 10.1016/j.yjmcc.2006.05.017
Fung E, Fiscus RR. Adrenomedullin induces direct (endothelium-independent) vasorelaxations and cyclic adenosine monophosphate elevations that are synergistically enhanced by brain natriuretic peptide in isolated rings of rat thoracic aorta. J Cardiovasc Pharm. 2003;41:849–55.
doi: 10.1097/00005344-200306000-00004
Qian P, Wang Q, Wang FZ, Dai HB, Wang HY, Gao Q, et al. Adrenomedullin Improves Cardiac Remodeling and Function in Obese Rats with Hypertension. Pharm (Basel). 2022;15:719.
Estrada IA, Donthamsetty R, Debski P, Zhou MH, Zhang SL, Yuan JX, et al. STIM1 restores coronary endothelial function in type 1 diabetic mice. Circ Res. 2012;111:1166–75.
pubmed: 22896585
pmcid: 3627729
doi: 10.1161/CIRCRESAHA.112.275743
Konior A, Schramm A, Czesnikiewicz-Guzik M, Guzik TJ. NADPH oxidases in vascular pathology. Antioxid Redox Signal. 2014;20:2794–814.
pubmed: 24180474
pmcid: 4026218
doi: 10.1089/ars.2013.5607
Boden G. Obesity and free fatty acids. Endocrinol Metab Clin North Am. 2008;37:635–46. viii-ix
pubmed: 18775356
pmcid: 2596919
doi: 10.1016/j.ecl.2008.06.007
Wang M, Chen Y, Xiong Z, Yu S, Zhou B, Ling Y, et al. Ginsenoside Rb1 inhibits free fatty acids‑induced oxidative stress and inflammation in 3T3‑L1 adipocytes. Mol Med Rep. 2017;16:9165–72.
pubmed: 28990058
doi: 10.3892/mmr.2017.7710
Zhang S, Patel A, Moorthy B, Shivanna B. Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells. Biochem Biophys Res Commun. 2015;464:1048–53.
pubmed: 26196743
pmcid: 4558361
doi: 10.1016/j.bbrc.2015.07.067
Shimosawa T, Shibagaki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, et al. Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage. Circulation. 2002;105:106–11.
pubmed: 11772884
doi: 10.1161/hc0102.101399
Shimosawa T, Ogihara T, Matsui H, Asano T, Ando K, Fujita T. Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress. Hypertension. 2003;41:1080–5.
pubmed: 12668590
doi: 10.1161/01.HYP.0000066846.46422.2C
Ashizuka S, Kita T, Inatsu H, Kitamura K. Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease. Biomedicines. 2021;9:1068.
pubmed: 34440272
pmcid: 8391925
doi: 10.3390/biomedicines9081068
Gadkari TV, Cortes N, Madrasi K, Tsoukias NM, Joshi MS. Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension. Nitric Oxide. 2013;35:65–71.
pubmed: 23994446
doi: 10.1016/j.niox.2013.08.005
Cottam MA, Caslin HL, Winn NC, Hasty AH. Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice. Nat Commun. 2022;13:2950.
pubmed: 35618862
pmcid: 9135744
doi: 10.1038/s41467-022-30646-4
Kiran S, Rakib A, Kodidela S, Kumar S, Singh UP. High-Fat Diet-Induced Dysregulation of Immune Cells Correlates with Macrophage Phenotypes and Chronic Inflammation in Adipose Tissue. Cells. 2022;11:1327.
pubmed: 35456006
pmcid: 9031506
doi: 10.3390/cells11081327
Steven S, Dib M, Hausding M, Kashani F, Oelze M, Kröller-Schön S, et al. CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice. Cardiovasc Res. 2018;114:312–23.
pubmed: 29036612
doi: 10.1093/cvr/cvx197
Matson BC, Caron KM. Adrenomedullin and endocrine control of immune cells during pregnancy. Cell Mol Immunol. 2014;11:456–9.
pubmed: 25132453
pmcid: 4197213
doi: 10.1038/cmi.2014.71
Han J, Wan Q, Seo GY, Kim K, El Baghdady S, Lee JH, et al. Hypoxia induces adrenomedullin from lung epithelia, stimulating ILC2 inflammation and immunity. J Exp Med. 2022;219:e20211985.
pubmed: 35532553
pmcid: 9093746
doi: 10.1084/jem.20211985
Nomura I, Abe J, Noma S, Saito H, Gao B, Wheeler G, et al. Adrenomedullin is highly expressed in blood monocytes associated with acute Kawasaki disease: a microarray gene expression study. Pediatr Res. 2005;57:49–55.
pubmed: 15531734
doi: 10.1203/01.PDR.0000147745.52711.DD
Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci. 2017;24:50.
pubmed: 28750629
pmcid: 5530532
doi: 10.1186/s12929-017-0357-5
Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol. 2005;25:2480–7.
pubmed: 16141406
doi: 10.1161/01.ATV.0000184759.91369.f8
Imai Y, Shindo T, Maemura K, Sata M, Saito Y, Kurihara Y, et al. Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression. Arterioscler Thromb Vasc Biol. 2002;22:1310–5.
pubmed: 12171793
doi: 10.1161/01.ATV.0000024685.92243.E7
Balakumar P, Kathuria S, Taneja G, Kalra S, Mahadevan N. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol. 2012;52:83–92.
pubmed: 21968328
doi: 10.1016/j.yjmcc.2011.09.014
Bruno RM, Masi S, Taddei M, Taddei S, Virdis A. Essential Hypertension and Functional Microvascular Ageing. High Blood Press Cardiovasc Prev. 2018;25:35–40.
pubmed: 29313304
doi: 10.1007/s40292-017-0245-9