{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T20:31:20Z","timestamp":1781382680856,"version":"3.54.1"},"reference-count":51,"publisher":"American Society for Clinical Investigation","issue":"15","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F31HL134196"],"award-info":[{"award-number":["F31HL134196"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-135827"],"award-info":[{"award-number":["HL-135827"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-119012"],"award-info":[{"award-number":["HL-119012"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-089297"],"award-info":[{"award-number":["HL-089297"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-07227"],"award-info":[{"award-number":["HL-07227"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["16SFRN28620000"],"award-info":[{"award-number":["16SFRN28620000"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,9]]},"abstract":"<jats:p>\n                    MicroRNAs (miRs) posttranscriptionally regulate mRNA and its translation into protein, and are considered master controllers of genes modulating normal physiology and disease. There is growing interest in how miRs change with drug treatment, and leveraging this for precision guided therapy. Here we contrast 2 closely related therapies, inhibitors of phosphodiesterase type 5 or type 9 (PDE5-I, PDE9-I), given to mice subjected to sustained cardiac pressure overload (PO). Both inhibitors augment cyclic guanosine monophosphate (cGMP) to activate protein kinase G, with PDE5-I regulating nitric oxide (NO) and PDE9-I natriuretic peptide\u2013dependent signaling. While both produced strong phenotypic improvement of PO pathobiology, they surprisingly showed binary differences in miR profiles; PDE5-I broadly reduces more than 120 miRs, including nearly half those increased by PO, whereas PDE9-I has minimal impact on any miR (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001). The disparity evolves after pre-miR processing and is organ specific. Lastly, even enhancing NO-coupled cGMP by different methods leads to altered miR regulation. Thus, seemingly similar therapeutic interventions can be barcoded by profound differences in miR signatures, and reversing disease-associated miR changes is not required for therapy success.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.121739","type":"journal-article","created":{"date-parts":[[2018,8,8]],"date-time":"2018-08-08T11:01:03Z","timestamp":1533726063000},"source":"Crossref","is-referenced-by-count":24,"title":["Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease"],"prefix":"10.1172","volume":"3","author":[{"given":"Kristen M.","family":"Kokkonen-Simon","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."},{"name":"Cellular and Molecular Medicine Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7255-7463","authenticated-orcid":true,"given":"Amir","family":"Saberi","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1205-3252","authenticated-orcid":true,"given":"Taishi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4970-8988","authenticated-orcid":true,"given":"Mark J.","family":"Ranek","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangshuo","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djahida","family":"Bedja","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc K.","family":"Halushka","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Ik","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-2299","authenticated-orcid":true,"given":"David A.","family":"Kass","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA."},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3838"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009008"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.117.004278"},{"key":"B4","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/164_2016_99","article-title":"Noncoding RNAs in heart failure","volume":"243","author":"Dangwal","year":"2017","journal-title":"Handb Exp Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1139089"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608791103"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm1582"},{"issue":"2","key":"B8","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.113.000078","article-title":"Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling","volume":"2","author":"Karakikes","year":"2013","journal-title":"J Am Heart Assoc"},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms2090","article-title":"The miRNA-212\/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy","volume":"3","author":"Ucar","year":"2012","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.030932"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.495"},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-015-0555-z","article-title":"Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNF\u03b1","volume":"17","author":"Castro-Villegas","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0000000000000379"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature14332"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nm1175"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2568"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-3-r13"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24144"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.117.004740"},{"issue":"Pt 14","key":"B20","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1242\/jcs.067165","article-title":"Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy","volume":"123","author":"Li","year":"2010","journal-title":"J Cell Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.04.018"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2015.95"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000203"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36154"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-010-9169-7"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs001"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.132"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.05.079"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206432109"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2310\/JIM.0b013e3182819ac6"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12380"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.051625598"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.2174\/138161206778343064"},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2164-8-172","article-title":"microRNA expression in the aging mouse lung","volume":"8","author":"Williams","year":"2007","journal-title":"BMC Genomics"},{"key":"B35","article-title":"Changes in miRNA in the lung and whole blood after whole thorax irradiation in rats","volume":"7","author":"Gao","year":"2017","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35620"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.08.017"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-015-0550-9","article-title":"The effects of phosphodiesterase-5 inhibitor sildenafil against post-resuscitation myocardial and intestinal microcirculatory dysfunction by attenuating apoptosis and regulating microRNAs expression: essential role of nitric oxide syntheses signaling","volume":"13","author":"Zhang","year":"2015","journal-title":"J Transl Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4252"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.259242"},{"issue":"1","key":"B41","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1161\/01.RES.0000152262.22968.72","article-title":"cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism","volume":"96","author":"Takimoto","year":"2005","journal-title":"Circ Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010716-104756"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nature21025"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143066"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-10-r106"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-120213-092023"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3317"},{"key":"B49","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B51","unstructured":"Carlson M. KEGG.db: A set of annotation maps for KEGG. R package version 3.2.3. Bioconductor. https:\/\/bioconductor.org\/packages\/release\/data\/annotation\/html\/KEGG.db.html Accessed July 24, 2018"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/121739\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:57:59Z","timestamp":1779195479000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/121739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,9]]},"references-count":51,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2018,8,9]]},"published-print":{"date-parts":[[2018,8,9]]}},"alternative-id":["10.1172\/jci.insight.121739"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.121739","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,9]]},"article-number":"e121739"}}