{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:29:48Z","timestamp":1788582588743,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institutional Development Award","award":["P20GM130460"],"award-info":[{"award-number":["P20GM130460"]}]},{"name":"University of Mississippi School of Pharmacy and the Department of BioMolecular Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This study examined how RAGE and Rap1a influence cardiac responses to AngII using wild-type (WT), RAGE knockout (RAGE KO), and Rap1a knockout (RapKO) mice. Cardiac structure and function were evaluated following AngII infusion. RapKO mice were protected from AngII-induced hypertrophy, whereas RAGE KO mice exhibited altered remodeling patterns. AngII consistently increased left ventricular wall thickness across all genotypes, indicating that structural remodeling is primarily treatment-driven. Measures of cardiac output and stroke volume also changed significantly with AngII, suggesting hemodynamic load as a key driver of functional adaptation. In contrast, diastolic functional parameters were genotype-dependent and remained stable with AngII exposure, demonstrating an intrinsic influence of RAGE and Rap1a on myocardial relaxation. These findings highlight distinct roles for RAGE and Rap1a in modulating hypertensive cardiac remodeling and may parallel human hypertensive heart disease, where increased RAGE and Rap1a expression associate with fibrosis and impaired relaxation. Targeting the crosstalk between the RAGE-AT1R axis and the cAMP-EPAC-Rap1a pathway may offer therapeutic potential to reduce adverse cardiac remodeling in hypertension.<\/jats:p>","DOI":"10.3390\/cells14221834","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T08:59:46Z","timestamp":1763715586000},"page":"1834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Knocking Out Rap1a Attenuates Cardiac Remodeling and Fibrosis in a Male Murine Model of Angiotensin II-Induced Hypertension"],"prefix":"10.3390","volume":"14","author":[{"given":"Cody S.","family":"Porter","sequence":"first","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa T.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can\u2019Torrius","family":"Lacey","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3122-5363","authenticated-orcid":false,"given":"Mason T.","family":"Hickel","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8920-8809","authenticated-orcid":false,"suffix":"Jr.","given":"James A.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7848027","DOI":"10.1155\/2021\/7848027","article-title":"Rap1GAP Mediates Angiotensin II-Induced Cardiomyocyte Hypertrophy by Inhibiting Autophagy and Increasing Oxidative Stress","volume":"2021","author":"Gao","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1091\/mbc.E18-07-0422","article-title":"Mechanosensitive Rap1 Activation Promotes Barrier Function of Lung Vascular Endothelium under Cyclic Stretch","volume":"30","author":"Ke","year":"2019","journal-title":"Mol. Biol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Pan, Y., Liu, J., Ren, J., Luo, Y., and Sun, X. (2022). Epac: A Promising Therapeutic Target for Vascular Diseases: A Review. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.929152"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1152\/physrev.00038.2017","article-title":"Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology","volume":"98","author":"Forrester","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.yjmcc.2016.06.001","article-title":"Physiological and Pathological Cardiac Hypertrophy","volume":"97","author":"Shimizu","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"72","DOI":"10.31083\/j.rcm2502072","article-title":"Molecular Mechanisms Underlying Vascular Remodeling in Hypertension","volume":"25","author":"Zeng","year":"2024","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bhullar, S.K., and Dhalla, N.S. (2022). Angiotensin II-Induced Signal Transduction Mechanisms for Cardiac Hypertrophy. Cells, 11.","DOI":"10.3390\/cells11213336"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yokoyama, S., Kawai, T., Yamamoto, K., Yibin, H., Yamamoto, H., Kakino, A., Takeshita, H., Nozato, Y., Fujimoto, T., and Hongyo, K. (2021). RAGE Ligands Stimulate Angiotensin II Type I Receptor (AT1) via RAGE\/AT1 Complex on the Cell Membrane. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-85312-4"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.2337\/diabetes.52.9.2381","article-title":"S100B-RAGE-Mediated Augmentation of Angiotensin II-Induced Activation of JAK2 in Vascular Smooth Muscle Cells Is Dependent on PLD2","volume":"52","author":"Shaw","year":"2003","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1758-5996-6-86","article-title":"Ramipril Inhibits AGE-RAGE-Induced Matrix Metalloproteinase-2 Activation in Experimental Diabetic Nephropathy","volume":"6","author":"Fukami","year":"2014","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.yjmcc.2007.07.044","article-title":"Upregulation of the Ligand\u2013RAGE Pathway via the Angiotensin II Type I Receptor Is Essential in the Pathogenesis of Diabetic Atherosclerosis","volume":"43","author":"Ihara","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.atherosclerosis.2022.02.022","article-title":"Soluble RAGE Attenuates Ang II-Induced Arterial Calcification via Inhibiting AT1R-HMGB1-RAGE Axis","volume":"346","author":"Jeong","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Burr, S.D., and Stewart, J.A. (2021). Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE\/RAGE Cascade. Cells, 10.","DOI":"10.3390\/cells10061286"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1182\/blood-2008-02-138438","article-title":"Role of the Small GTPase Rap1 for Integrin Activity Regulation in Endothelial Cells and Angiogenesis","volume":"113","author":"Carmona","year":"2009","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Qrareya, A.N., Wise, N.S., Hodges, E.R., Mahdi, F., Stewart, J.A., and Paris, J.J. (2022). HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice. Viruses, 14.","DOI":"10.3390\/v14102191"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tan, Y.-Q., Li, J., and Chen, H.-W. (2022). Epac, a Positive or Negative Signaling Molecule in Cardiovascular Diseases. Biomed. Pharmacother., 148.","DOI":"10.1016\/j.biopha.2022.112726"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1042\/BST20130253","article-title":"CAMP Signalling in the Vasculature: The Role of Epac (Exchange Protein Directly Activated by CAMP)","volume":"42","author":"Roberts","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1182\/blood-2004-05-1987","article-title":"Regulation of Vascular Endothelial Barrier Function by Epac, a CAMP-Activated Exchange Factor for Rap GTPase","volume":"105","author":"Cullere","year":"2005","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Flentje, A., Kalsi, R., and Monahan, T.S. (2019). Small GTPases and Their Role in Vascular Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040917"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/cvr\/cvq086","article-title":"Role of GTPases in Control of Microvascular Permeability","volume":"87","author":"Spindler","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3892\/mmr.2024.13332","article-title":"Roles of Small GTPases in Cardiac Hypertrophy (Review)","volume":"30","author":"Wang","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"F1260","DOI":"10.1152\/ajprenal.00069.2014","article-title":"Modulation of Angiotensin II-Induced Inflammatory Cytokines by the Epac1-Rap1A-NHE3 Pathway: Implications in Renal Tubular Pathobiology","volume":"306","author":"Xie","year":"2014","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41401-021-00689-2","article-title":"Epac Activation Ameliorates Tubulointerstitial Inflammation in Diabetic Nephropathy","volume":"43","author":"Yang","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1161\/CIRCRESAHA.115.306529","article-title":"Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease","volume":"118","author":"Fazal","year":"2016","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1476-5381.2009.00458.x","article-title":"The Role of Epac Proteins, Novel CAMP Mediators, in the Regulation of Immune, Lung and Neuronal Function","volume":"159","author":"Grandoch","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev.pharmtox.010909.105714","article-title":"Epac: Defining a New Mechanism for CAMP Action","volume":"50","author":"Gloerich","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1172\/JCI64784","article-title":"Epac1-Dependent Phospholamban Phosphorylation Mediates the Cardiac Response to Stresses","volume":"124","author":"Okumura","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_28","first-page":"1766","article-title":"Identification of a Pharmacological Inhibitor of Epac1 That Protects the Heart against Acute and Chronic Models of Cardiac Stress","volume":"115","author":"Laudette","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Laudette, M., Zuo, H., Lezoualc\u2019h, F., and Schmidt, M. (2018). Epac Function and CAMP Scaffolds in the Heart and Lung. J. Cardiovasc. Dev. Dis., 5.","DOI":"10.3390\/jcdd5010009"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bouvet, M., Blondeau, J.-P., and Lezoualc\u2019h, F. (2019). The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology. Cells, 8.","DOI":"10.3390\/cells8121543"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Burr, S.D., Harmon, M.B., and Stewart, J.A. (2020). The Impact of Diabetic Conditions and AGE\/RAGE Signaling on Cardiac Fibroblast Migration. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00112"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117569","DOI":"10.1016\/j.lfs.2020.117569","article-title":"Extracellular Matrix Components Isolated from Diabetic Mice Alter Cardiac Fibroblast Function through the AGE\/RAGE Signaling Cascade","volume":"250","author":"Burr","year":"2020","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Burr, S.D., and Stewart, J.A. (2021). Rap1a Overlaps the AGE\/RAGE Signaling Cascade to Alter Expression of \u03b1-SMA, p-NF-\u039aB, and p-PKC-\u03b6 in Cardiac Fibroblasts Isolated from Type 2 Diabetic Mice. Cells, 10.","DOI":"10.3390\/cells10030557"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"H203","DOI":"10.1152\/ajpheart.00038.2023","article-title":"Characterization of a Robust Mouse Model of Heart Failure with Preserved Ejection Fraction","volume":"325","author":"Matsiukevich","year":"2023","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1172\/JCI99987","article-title":"Transactivation of RAGE Mediates Angiotensin-Induced Inflammation and Atherogenesis","volume":"129","author":"Pickering","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"H733","DOI":"10.1152\/ajpheart.00339.2017","article-title":"Guidelines for Measuring Cardiac Physiology in Mice","volume":"314","author":"Lindsey","year":"2018","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1161\/01.RES.0000194325.31359.86","article-title":"CAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy","volume":"97","author":"Morel","year":"2005","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00018-016-2336-5","article-title":"The Role of Epac in the Heart","volume":"74","author":"Fujita","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2337\/diacare.29.02.06.dc05-2048","article-title":"Insulin Signaling, Glucose Metabolism, and the Angiotensin II Signaling System: Studies in Bartter\u2019s\/Gitelman\u2019s Syndromes","volume":"29","author":"Davis","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1210\/jc.2009-2587","article-title":"Angiotensin II Enhances Insulin-Stimulated Whole-Body Glucose Disposal but Impairs Insulin-Induced Capillary Recruitment in Healthy Volunteers","volume":"95","author":"Jonk","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/hr.2010.99","article-title":"Angiotensin II Receptor Blockers and Insulin Resistance","volume":"33","author":"Ciccarelli","year":"2010","journal-title":"Hypertens. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1161\/01.HYP.30.5.1156","article-title":"Angiotensin II Affects Basal, Pulsatile, and Glucose-Stimulated Insulin Secretion in Humans","volume":"30","author":"Fliser","year":"1997","journal-title":"Hypertension"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17985","DOI":"10.1073\/pnas.0605545103","article-title":"Angiotensin II Causes Hypertension and Cardiac Hypertrophy through Its Receptors in the Kidney","volume":"103","author":"Crowley","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin II Cell Signaling: Physiological and Pathological Effects in the Cardiovascular System","volume":"292","author":"Mehta","year":"2007","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.yjmcc.2006.04.019","article-title":"17\u03b2-Estradiol Modulation of Angiotensin II-Stimulated Response in Cardiac Fibroblasts","volume":"41","author":"Stewart","year":"2006","journal-title":"J. Mol. Cell. Cardiol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1834\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:33:49Z","timestamp":1763980429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":45,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cells14221834"],"URL":"https:\/\/doi.org\/10.3390\/cells14221834","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]}}}