{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T01:13:29Z","timestamp":1773796409262,"version":"3.50.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008899","name":"University of South Carolina","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008899","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> \u03b1-CGRP (alpha-calcitonin gene related peptide) is a cardioprotective neuropeptide. Our recent study demonstrated that the administration of native \u03b1-CGRP, using osmotic mini-pumps, protected against transverse aortic constriction (TAC) pressure-induced heart failure in mice. However, the short half-life of peptides and the non-applicability of osmotic pumps in humans limits the use of \u03b1-CGRP as a therapeutic agent for heart failure (HF). Here, we sought to comprehensively study a novel \u03b1-CGRP delivery system using alginate microcapsules to determine its bioavailability <jats:italic>in vivo<\/jats:italic> and to test for cardioprotective effects in HF mice.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Native \u03b1-CGRP filled alginate microcapsules (200\u00a0\u00b5m diameter) were prepared using an electrospray method. The prepared alginate-\u03b1-CGRP microcapsules were incubated with rat cardiac H9c2 cells, mouse cardiac HL-1 cells, and human umbilical vein endothelial cells (HUVECs), and the cytotoxicity of the alginate-\u03b1-CGRP microcapsules was measured by a trypan-blue cell viability assay and a calcium dye fluorescent based assay. The efficacy of the alginate-\u03b1-CGRP microcapsules was tested in a TAC-pressure overload mouse model of heart failure. Male C57BL6 mice were divided into four groups: sham, sham-alginate-\u03b1-CGRP, TAC-only, and TAC-alginate-\u03b1-CGRP, and the TAC procedure was performed in the TAC-only and TAC-alginate-\u03b1-CGRP groups of mice to induce pressure-overload heart failure. After 2 or 15\u00a0days post-TAC, alginate-\u03b1-CGRP microcapsules (containing an \u03b1-CGRP dose of 6\u00a0mg\/kg\/mouse) were administered subcutaneously on alternate days, for 28\u00a0days, and echocardiography was performed weekly. After 28\u00a0days of peptide delivery, the mice were sacrificed and their hearts were collected for histological and biochemical analyses.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Our <jats:italic>in vitro<\/jats:italic> cell culture assays showed that alginate-\u03b1-CGRP microcapsules did not affect the viability of the cell lines tested. The alginate-\u03b1-CGRP microcapsules released their peptides for an extended period of time. Our echocardiography, biochemical, and histology data from HF mice demonstrated that the administration of alginate-\u03b1-CGRP microcapsules significantly improved all cardiac parameters examined in TAC-mice. When compared to sham mice, TAC significantly decreased cardiac functions (as determined by fraction shortening and ejection fraction) and markedly increased heart and lung weight, left ventricle (LV) cardiac cell size, cardiac apoptosis, and oxidative stress. In contrast, the administration of alginate-\u03b1-CGRP microcapsules significantly attenuated the increased heart and lung weight, LV cardiac cell size, apoptosis, and oxidative stress in TAC mice.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our results demonstrate that the encapsulation of \u03b1-CGRP in an alginate polymer is an effective strategy to improve peptide bioavailability in plasma and increase the duration of the therapeutic effect of the peptide throughout the treatment period. Furthermore, alginate mediates \u03b1-CGRP delivery, either prior to the onset or after the initiation of the symptom progression of pressure-overload, improves cardiac function, and protects hearts against pressure-induced HF.<\/jats:p>","DOI":"10.3389\/fphar.2020.602952","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T20:43:09Z","timestamp":1612298589000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["A Novel Alginate-Based Delivery System for the Prevention and Treatment of Pressure-Overload Induced Heart Failure"],"prefix":"10.3389","volume":"11","author":[{"given":"Ambrish","family":"Kumar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa","family":"Belhaj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald J.","family":"DiPette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay D.","family":"Potts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"H1525","DOI":"10.1152\/ajpheart.00874.2012","article-title":"Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart","volume":"304","author":"Al-Rubaiee","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"R425","DOI":"10.1152\/ajpregu.1990.258.2.R425","article-title":"Hemodynamic effects of calcitonin gene-related peptide in spontaneously hypertensive rats","volume":"258","author":"Ando","year":"1990","journal-title":"Am. J. Physiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1167\/tvst.7.2.3","article-title":"Encapsulated cell technology-based delivery of a complement inhibitor reduces choroidal neovascularization in a mouse model","volume":"7","author":"Annamalai","year":"2018","journal-title":"Transl Vis Sci Technol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1161\/CIRCULATIONAHA.117.028388","article-title":"A novel \u03b1-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure","volume":"136","author":"Aubdool","year":"2017","journal-title":"Circulation."},{"key":"B5","doi-asserted-by":"publisher","first-page":"157","DOI":"10.3791\/60162","article-title":"Encapsulated cell technology for the delivery of biologics to the mouse eye","volume":"30","author":"Belhaj","year":"2020","journal-title":"JoVE."},{"key":"B6","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1161\/01.HYP.0000168926.44648.ed","article-title":"Role of calcitonin gene-related peptide in hypertension-induced renal damage","volume":"46","author":"Bowers","year":"2005","journal-title":"Hypertension."},{"key":"B7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/313054a0","article-title":"Calcitonin gene-related peptide is a potent vasodilator","volume":"313","author":"Brain","year":"1985","journal-title":"Nature."},{"key":"B8","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.ejphar.2005.12.039","article-title":"The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts","volume":"531","author":"Chai","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1097\/00000441-198902000-00001","article-title":"Dose-dependent systemic and regional hemodynamic effects of calcitonin gene-related peptide","volume":"297","author":"Dipette","year":"1989","journal-title":"Am. J. Med. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"III142","DOI":"10.1161\/01.hyp.9.6_pt_2.iii142","article-title":"Systemic and regional hemodynamic effects of calcitonin gene-related peptide","volume":"9","author":"Dipette","year":"1987","journal-title":"Hypertension."},{"key":"B11","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/0002-9149(92)90736-i","article-title":"Effects of calcitonin gene-related peptide on cardiac contractility, coronary hemodynamics and myocardial energetics in idiopathic dilated cardiomyopathy","volume":"70","author":"Dubois-Rande","year":"1992","journal-title":"Am. J. Cardiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1161\/01.hyp.29.1.248","article-title":"Calcitonin gene-related peptide is a depressor in NG-nitro-L-arginine methyl ester-induced hypertension during pregnancy","volume":"29","author":"Gangula","year":"1997","journal-title":"Hypertension."},{"key":"B13","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1093\/cvr\/24.3.239","article-title":"Improved cardiac performance with human calcitonin gene related peptide in patients with congestive heart failure","volume":"24","author":"Gennari","year":"1990","journal-title":"Cardiovasc. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.jconrel.2004.02.021","article-title":"Sustained delivery of vascular endothelial growth factor with alginate beads","volume":"96","author":"Gu","year":"2004","journal-title":"J. Contr. Release."},{"key":"B15","doi-asserted-by":"publisher","first-page":"H1291","DOI":"10.1152\/ajpheart.00749.2007","article-title":"Deletion of the mouse alpha-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury","volume":"294","author":"Huang","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1161\/hy09t1.095761","article-title":"Role of calcitonin gene-related peptide and substance P in Dahl-salt hypertension","volume":"38","author":"Katki","year":"2001","journal-title":"Hypertension."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.3389\/fphys.2018.01249","article-title":"The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects","volume":"9","author":"Kee","year":"2018","journal-title":"Front. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"11709","DOI":"10.18632\/oncotarget.2606","article-title":"Metformin impairs Rho GTPase signaling to induce apoptosis in neuroblastoma cells and inhibits growth of tumors in the xenograft mouse model of neuroblastoma","volume":"5","author":"Kumar","year":"2014","journal-title":"Oncotarget."},{"key":"B19","doi-asserted-by":"publisher","first-page":"821","DOI":"10.3389\/fphys.2019.00821","article-title":"Protective role of \u03b1-calcitonin gene-related peptide in cardiovascular diseases","volume":"10","author":"Kumar","year":"","journal-title":"Front. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1124\/mol.111.071126","article-title":"Resveratrol restores Nrf2 level and prevents ethanol-induced toxic effects in the cerebellum of a rodent model of fetal alcohol spectrum disorders","volume":"80","author":"Kumar","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e14269","DOI":"10.14814\/phy2.14269","article-title":"Alpha-calcitonin gene-related peptide prevents pressure-overload induced heart failure: role of apoptosis and oxidative stress","volume":"7","author":"Kumar","year":"","journal-title":"Phys. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.progpolymsci.2011.06.003","article-title":"Alginate: properties and biomedical applications","volume":"37","author":"Lee","year":"2012","journal-title":"Prog. Polym. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.regpep.2013.06.008","article-title":"Alpha-calcitonin gene-related peptide is protective against pressure overload-induced heart failure","volume":"185","author":"Li","year":"2013","journal-title":"Regul. Pept."},{"key":"B24","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.tips.2016.06.002","article-title":"Wiping out CGRP: potential cardiovascular risks","volume":"37","author":"Maassenvandenbrink","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/0140-6736(90)90040-c","article-title":"Plasma CGRP in acute myocardial infarction","volume":"335","author":"Mair","year":"1990","journal-title":"Lancet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1017\/S143192761201389X","article-title":"Characterization of polymeric microcapsules containing a low molecular weight peptide for controlled release","volume":"19","author":"Moore","year":"","journal-title":"Microsc. Microanal."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e86570","DOI":"10.1371\/journal.pone.0086570","article-title":"Impact of the controlled release of a connexin 43 peptide on corneal wound closure in an STZ model of type I diabetes","volume":"9","author":"Moore","year":"2014","journal-title":"PloS One."},{"key":"B28","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/978-1-62703-604-7_10","article-title":"Microencapsulation of stem cells to study cellular interactions","volume":"1066","author":"Moore","year":"","journal-title":"Methods Mol. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1152\/physrev.00034.2013","article-title":"Calcitonin gene-related peptide: physiology and pathophysiology","volume":"94","author":"Russell","year":"2014","journal-title":"Physiol. Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.jocn.2012.07.006","article-title":"Calcitonin-gene related peptide and cerebral vasospasm","volume":"20","author":"Schebesch","year":"2013","journal-title":"J. Clin. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1161\/CIRCRESAHA.119.315429","article-title":"Blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced \u03b1CGRP (\u03b1 calcitonin gene-related peptide) in chronically hypertensive mice","volume":"125","author":"Skaria","year":"2019","journal-title":"Circ. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1161\/01.hyp.21.6.1010","article-title":"Calcitonin gene-related peptide gene expression in the spontaneously hypertensive rat","volume":"21","author":"Supowit","year":"1993","journal-title":"Hypertension."},{"key":"B33","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1161\/01.HYP.0000151130.34874.fa","article-title":"Calcitonin gene-related peptide protects against hypertension-induced heart and kidney damage","volume":"45","author":"Supowit","year":"2005","journal-title":"Hypertension."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1161\/01.hyp.26.6.1177","article-title":"Regulation of neuronal calcitonin gene-related peptide expression. Role of increased blood pressure","volume":"26","author":"Supowit","year":"1995","journal-title":"Hypertension."},{"key":"B35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ejpb.2010.09.016","article-title":"Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin","volume":"77","author":"Zhang","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.602952\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T20:43:11Z","timestamp":1612298591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.602952\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,2]]},"references-count":35,"alternative-id":["10.3389\/fphar.2020.602952"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2020.602952","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,2]]},"article-number":"602952"}}