{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:11:14Z","timestamp":1787656274162,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T00:00:00Z","timestamp":1591142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. Aim: To test if the PDE5A-cGMP-PKG pathway may contribute to burn-induced heart dysfunction. Methods: Sprague\u2013Dawley rats were divided four groups: sham; sham\/sildenafil; 24 h post burn (60% total body surface area scald burn, harvested at 24 h post burn); and 24 h post burn\/sildenafil. We monitored heart function and oxidative adducts, as well as cardiac inflammatory, cardiac fibrosis and cardiac remodeling responses in vivo. Results: Sildenafil inhibited the burn-induced PDE5A mRNA level and increased the cGMP level and PKG activity, leading to the normalization of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), a decreased ROS level (H2O2), decreased oxidatively modified adducts (malonyldialdehyde [MDA], carbonyls), attenuated fibrogenesis as well as fibrosis gene expression (ANP, BNP, COL1A2, COL3A2, \u03b1SMA and \u03b1sk-Actin), and reduced inflammation and related gene expression (RELA, IL-18 and TGF-\u03b2) after the burn. Additionally, sildenafil treatment preserved left ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and recovered the oxidant\/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity). Conclusions: The PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction. Sildenafil treatment recovers burn-induced cardiac dysfunction.<\/jats:p>","DOI":"10.3390\/cells9061393","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T04:36:09Z","timestamp":1591245369000},"page":"1393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sildenafil Recovers Burn-Induced Cardiomyopathy"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5075-9272","authenticated-orcid":false,"given":"Jake J.","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Cummins","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi S.","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"ref_1","unstructured":"WHO (2020, June 02). Burns. Available online: https:\/\/www.who.int\/violence_injury_prevention\/other_injury\/burns\/en\/."},{"key":"ref_2","unstructured":"CDC (2020, June 02). Burn Prevention, Available online: https:\/\/www.cdc.gov\/safechild\/burns\/index.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1097\/BCR.0b013e3181e4d680","article-title":"Predicting prognosis in thermal burns with associated inhalational injury: A systematic review of prognostic factors in adult burn victims","volume":"31","author":"Colohan","year":"2010","journal-title":"J. Burn Care Res."},{"key":"ref_4","unstructured":"Lawrence, B.A., Zaloshnja, E., Miller, T.R., and Jones, P.R. (2009). Estimates of the Incidence and Costs of Fire-Related Injuries."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7902","DOI":"10.4049\/jimmunol.178.12.7902","article-title":"C5a-blockade improves burn-induced cardiac dysfunction","volume":"178","author":"Hoesel","year":"2007","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.pharmthera.2009.02.009","article-title":"Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics","volume":"122","author":"Tsai","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1113\/jphysiol.2001.014126","article-title":"Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes","volume":"540","author":"Layland","year":"2002","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.tips.2011.02.019","article-title":"Phosphodiesterases and cardiac cGMP: Evolving roles and controversies","volume":"32","author":"Zhang","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_9","first-page":"248","article-title":"Phosphodiesterases and cyclic GMP regulation in heart muscle","volume":"27","author":"Lee","year":"2012","journal-title":"Physiology (Bethesda)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/164_2016_82","article-title":"Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease","volume":"243","author":"Kim","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1124\/jpet.108.137422","article-title":"Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil","volume":"326","author":"Nagayama","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Andersson, K.E. (2018). PDE5 inhibitors-pharmacology and clinical applications 20 years after sildenafil discovery. Br. J. Pharmacol.","DOI":"10.1111\/bph.14205"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wen, J.J., Cummins, C.B., Szczesny, B., and Radhakrishnan, R.S. (2020). Cardiac Dysfunction after Burn Injury: Role of the AMPK-SIRT1-PGC1alpha-NFE2L2-ARE Pathway. J. Am. Coll. Surg.","DOI":"10.1016\/j.jamcollsurg.2019.12.029"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wen, J.J., Cummins, C.B., and Radhakrishnan, R.S. (2020). Burn-Induced Cardiac Mitochondrial Dysfunction via Interruption of the PDE5A-cGMP-PKG Pathway. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072350"},{"key":"ref_15","first-page":"190","article-title":"Nephrilin peptide modulates a neuroimmune stress response in rodent models of burn trauma and sepsis","volume":"3","author":"Mascarenhas","year":"2013","journal-title":"Int. J. Burns Trauma"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1097\/SHK.0000000000000935","article-title":"Burn Trauma Acutely Increases the Respiratory Capacity and Function of Liver Mitochondria","volume":"49","author":"Bohanon","year":"2018","journal-title":"Shock"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H1371","DOI":"10.1152\/ajpheart.00553.2013","article-title":"High-frequency speckle tracking echocardiography in the assessment of left ventricular function and remodeling after murine myocardial infarction","volume":"306","author":"Bhan","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1089\/ars.2016.6831","article-title":"Inhibition of NFE2L2-Antioxidant Response Element Pathway by Mitochondrial Reactive Oxygen Species Contributes to Development of Cardiomyopathy and Left Ventricular Dysfunction in Chagas Disease","volume":"27","author":"Wen","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wen, J.J., and Garg, N.J. (2018). Manganese superoxide dismutase deficiency exacerbates the mitochondrial ROS production and oxidative damage in Chagas disease. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006687"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1097\/SHK.0000000000001037","article-title":"Severe Burn-Induced Inflammation and Remodeling of Achilles Tendon in a Rat Model","volume":"50","author":"Hernandez","year":"2018","journal-title":"Shock"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1172\/JCI80275","article-title":"Prevention of PKG1alpha oxidation augments cardioprotection in the stressed heart","volume":"125","author":"Nakamura","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1253\/circj.CJ-12-0664","article-title":"Cyclic GMP-dependent signaling in cardiac myocytes","volume":"76","author":"Takimoto","year":"2012","journal-title":"Circ. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s003800200032","article-title":"Enhanced activities and gene expression of phosphodiesterase types 3 and 4 in pressure-induced congestive heart failure","volume":"16","author":"Takahashi","year":"2002","journal-title":"Heart Vessels"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e012273","DOI":"10.1161\/JAHA.119.012273","article-title":"Phosphodiesterase 5 Associates With beta2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts","volume":"8","author":"West","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.jacbts.2016.04.005","article-title":"Chemotherapeutic efficacy of phosphodiesterase inhibitors in chagasic cardiomyopathy","volume":"1","author":"Wen","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1136\/heartjnl-2017-312865","article-title":"Phosphodiesterase-5 inhibitors and the heart: Compound cardioprotection?","volume":"104","author":"Hutchings","year":"2018","journal-title":"Heart"},{"key":"ref_27","first-page":"CD012621","article-title":"Phosphodiesterase 5 inhibitors for pulmonary hypertension","volume":"1","author":"Barnes","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Guillory, A.N., Clayton, R.P., Herndon, D.N., and Finnerty, C.C. (2016). Cardiovascular Dysfunction Following Burn Injury: What We Have Learned from Rat and Mouse Models. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010053"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.amjcard.2017.06.012","article-title":"The Nitric Oxide Pathway in Pulmonary Vascular Disease","volume":"120","author":"Klinger","year":"2017","journal-title":"Am. J. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1161\/CIRCRESAHA.107.162511","article-title":"Phosphodiesterase type 5: Expanding roles in cardiovascular regulation","volume":"101","author":"Kass","year":"2007","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neuint.2017.10.015","article-title":"Icariside II, a PDE5 inhibitor from Epimedium brevicornum, promotes neuron-like pheochromocytoma PC12 cell proliferation via activating NO\/cGMP\/PKG pathway","volume":"112","author":"Gao","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S2352-4642(17)30122-0","article-title":"Long-term effect of critical illness after severe paediatric burn injury on cardiac function in adolescent survivors: An observational study","volume":"1","author":"Hundeshagen","year":"2017","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-kappaB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb Perspect Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.immuni.2005.04.006","article-title":"A stress-induced, superoxide-mediated caspase-1 activation pathway causes plasma IL-18 upregulation","volume":"22","author":"Sekiyama","year":"2005","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1073\/pnas.97.2.734","article-title":"IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1","volume":"97","author":"Fantuzzi","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/JLB.1HI1017-396RR","article-title":"Frontline Science: IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy","volume":"104","author":"Li","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_37","first-page":"2291","article-title":"Dual roles of IL-18 in colitis through regulation of the function and quantity of goblet cells","volume":"43","author":"Pu","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3389\/fimmu.2013.00289","article-title":"Interleukin-18 and IL-18 binding protein","volume":"4","author":"Dinarello","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.yjmcc.2010.10.033","article-title":"Transforming growth factor (TGF)-beta signaling in cardiac remodeling","volume":"51","author":"Dobaczewski","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1136\/pgmj.2008.069831","article-title":"Transforming growth factor beta1 signalling, wound healing and repair: A multifunctional cytokine with clinical implications for wound repair, a delicate balance","volume":"85","author":"Klass","year":"2009","journal-title":"Postgrad. Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00015.2005","article-title":"Function of cGMP-dependent protein kinases as revealed by gene deletion","volume":"86","author":"Hofmann","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1161\/CIRCULATIONAHA.109.906818","article-title":"Oxidative stress regulates left ventricular PDE5 expression in the failing heart","volume":"121","author":"Lu","year":"2010","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1464-410X.2005.05643.x","article-title":"Sildenafil inhibits the formation of superoxide and the expression of gp47 NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells","volume":"96","author":"Koupparis","year":"2005","journal-title":"BJU Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1161\/CIRCULATIONAHA.105.540500","article-title":"Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans","volume":"112","author":"Borlaug","year":"2005","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1038\/s41598-019-42592-1","article-title":"Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure","volume":"9","author":"Lawless","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1016\/j.jid.2018.01.037","article-title":"beta-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars","volume":"138","author":"Prasai","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/jbcr\/iry001","article-title":"Quantification of an Exercise Rehabilitation Program for Severely Burned Children: The Standard of Care at Shriners Hospitals for Children(R)-Galveston","volume":"39","author":"Rivas","year":"2018","journal-title":"J. Burn Care Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/6\/1393\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:35:26Z","timestamp":1760175326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/6\/1393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,3]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["cells9061393"],"URL":"https:\/\/doi.org\/10.3390\/cells9061393","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,3]]}}}