{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:42:23Z","timestamp":1760146943071,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FRN-166215"],"award-info":[{"award-number":["FRN-166215"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Manitoba","award":["FRN-166215"],"award-info":[{"award-number":["FRN-166215"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Growth hormone (GH) signaling is essential for heart development. Both GH deficiency and excess raise cardiovascular risk. Human (h) and mouse (m) GH differ structurally and functionally: hGH binds both the GH receptor (GHR) and prolactin receptor (PRLR), whereas mGH binds only GHR; thus, there is the potential for differential effects. We generated transgenic (hGH-TG) mice that produce pituitary hGH in response to hypothalamic signaling. These mice grow at the same rate as mGH-expressing wild-type (mGH-WT) mice but are smaller and have higher body fat. Echocardiography was used here to compare hGH-TG and mGH-WT mouse hearts. Male hGH-TG mice show a 48% lower left ventricular mass, 36% lower stroke volume, and 48% reduced cardiac output, resembling GH deficiency. Diastolic dysfunction, restrictive ventricular filling, and lower heart rate are suggested in hGH-TG mice. No significant differences in ejection fraction or fractional shortening were observed, even after high-fat diet (HFD) stress. HFD did not affect RNA markers of cardiac damage, although a possible association between B-type natriuretic peptide RNA levels and heart rate was detected. These observations suggest that diastolic dysfunction related to hGH and\/or low GH might be offset by a lower heart rate, while structural changes precede functional effects.<\/jats:p>","DOI":"10.3390\/ijms26010269","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T10:17:40Z","timestamp":1735640260000},"page":"269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diastolic Dysfunction with Normal Ejection Fraction and Reduced Heart Rate in Mice Expressing Human Growth Hormone and Displaying Signs of Growth Hormone Insufficiency"],"prefix":"10.3390","volume":"26","author":[{"given":"Yan","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5191-4628","authenticated-orcid":false,"given":"Vernon W.","family":"Dolinsky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elissavet","family":"Kardami","sequence":"additional","affiliation":[{"name":"Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1519-5475","authenticated-orcid":false,"given":"Peter A.","family":"Cattini","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1210\/edrv-15-5-555","article-title":"Growth hormone and the heart","volume":"15","author":"Sacca","year":"1994","journal-title":"Endocr. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1006\/jmcc.1999.1036","article-title":"Insulin-like growth factor I as a cardiac hormone: Physiological and pathophysiological implications in heart disease","volume":"31","author":"Ren","year":"1999","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s12020-014-0327-6","article-title":"GH and the cardiovascular system: An update on a topic at heart","volume":"48","author":"Isgaard","year":"2015","journal-title":"Endocrine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2174\/157340309788970306","article-title":"The GH\/IGF-1 Axis and Heart Failure","volume":"5","author":"Castellano","year":"2009","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Macvanin, M., Gluvic, Z., Radovanovic, J., Essack, M., Gao, X., and Isenovic, E.R. (2023). New insights on the cardiovascular effects of IGF-1. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1142644"},{"key":"ref_6","first-page":"1021","article-title":"The cardiovascular system in growth hormone excess and growth hormone deficiency","volume":"35","author":"Lombardi","year":"2012","journal-title":"J. Endocrinol. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Caicedo, D., Diaz, O., Devesa, P., and Devesa, J. (2018). Growth Hormone (GH) and Cardiovascular System. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010290"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1210\/en.2015-1686","article-title":"Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice","volume":"157","author":"Jara","year":"2016","journal-title":"Endocrinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1210\/en.2015-1097","article-title":"The forgotten lactogenic activity of growth hormone: Important implications for rodent studies","volume":"156","author":"Bartke","year":"2015","journal-title":"Endocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ghir.2018.09.001","article-title":"A useful model to compare human and mouse growth hormone gene chromosomal structure, expression and regulation, and immune tolerance of human growth hormone analogues","volume":"42\u201343","author":"Cattini","year":"2018","journal-title":"Growth Horm. IGF Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1210\/edrv.19.3.0334","article-title":"Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice","volume":"19","author":"Goffin","year":"1998","journal-title":"Endocr. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1210\/endo.133.1.8319561","article-title":"Visualization of gene expression of short and long forms of prolactin receptor in the rat","volume":"133","author":"Ouhtit","year":"1993","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e03797","DOI":"10.1016\/j.heliyon.2020.e03797","article-title":"Effects of prolactin on ventricular myocyte shortening and calcium transport in the streptozotocin-induced diabetic rat","volume":"6","author":"Howarth","year":"2020","journal-title":"Heliyon"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Papazoglou, A.S., and Leite, A.R. (2023). Prolactin levels and cardiovascular disease: A complicate relationship or a confounding association?. Eur. J. Prev. Cardiol., zwad176.","DOI":"10.1093\/eurjpc\/zwad176"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pirchio, R., Graziadio, C., Colao, A., Pivonello, R., and Auriemma, R.S. (2022). Metabolic effects of prolactin. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1015520"},{"key":"ref_16","first-page":"73","article-title":"Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high-fat diet-related insulin resistance, hepatic steatosis and adipose dysfunction","volume":"1","author":"Jin","year":"2024","journal-title":"J. Mol. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/s41592-018-0224-7","article-title":"Comparing phenotypic variation between inbred and outbred mice","volume":"15","author":"Tuttle","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Aldinger, K.A., Sokoloff, G., Rosenberg, D.M., Palmer, A.A., and Millen, K.J. (2009). Genetic variation and population substructure in outbred CD-1 mice: Implications for genome-wide association studies. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004729"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1016\/j.bbadis.2013.07.003","article-title":"Regulation of expression of atrial and brain natriuretic peptide, biomarkers for heart development and disease","volume":"1832","author":"Sergeeva","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1364\/BOE.410347","article-title":"Characterization of fibrillar collagen isoforms in infarcted mouse hearts using second harmonic generation imaging","volume":"12","author":"Sahu","year":"2021","journal-title":"Biomed. Opt. Express"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1159\/000438659","article-title":"Whole Transcriptome Analysis of Hypertension Induced Cardiac Injury Using Deep Sequencing","volume":"38","author":"Li","year":"2016","journal-title":"Cell Physiol. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41574-019-0280-9","article-title":"The effects of growth hormone on adipose tissue: Old observations, new mechanisms","volume":"16","author":"Kopchick","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_23","first-page":"E219","article-title":"Impaired cardiac performance in GH-deficient adults and its improvement after GH replacement","volume":"267","author":"Cittadini","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1136\/hrt.2003.029413","article-title":"Assessment of diastolic function: What the general cardiologist needs to know","volume":"91","author":"Mottram","year":"2005","journal-title":"Heart"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1161\/01.CIR.102.15.1788","article-title":"Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study","volume":"102","author":"Ommen","year":"2000","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yjmcc.2017.10.006","article-title":"Echocardiographic evaluation of diastolic function in mouse models of heart disease","volume":"114","author":"Schnelle","year":"2018","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_27","first-page":"102","article-title":"Supernormal left ventricular diastolic function in triathletes","volume":"28","author":"Claessens","year":"2001","journal-title":"Tex. Heart Inst. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"110615","DOI":"10.1016\/j.ejrad.2022.110615","article-title":"Left ventricular diastolic filling patterns in competitive triathletes with and without myocardial fibrosis by cardiac magnetic resonance time-volume analysis","volume":"158","author":"Chen","year":"2023","journal-title":"Eur. J. Radiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e15737","DOI":"10.1111\/echo.15737","article-title":"Evaluation of left ventricular stiffness with echocardiography","volume":"41","author":"Zhang","year":"2024","journal-title":"Echocardiography"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ngiam, J.N., Chew, N.W., Tan, B.Y., Sim, H.W., Kong, W.K.F., Yeo, T.C., Chowdhury, S.M., and Poh, K.K. (2020). Novel Echocardiography-Derived Left Ventricular Stiffness Index in Low-Flow Versus Normal-Flow Severe Aortic Stenosis with Preserved Left Ventricular Ejection Fraction. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65758-8"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1476-7120-11-12","article-title":"Transthoracic echocardiography reference values in juvenile and adult 129\/Sv mice","volume":"11","author":"Vinhas","year":"2013","journal-title":"Cardiovasc. Ultrasound"},{"key":"ref_32","first-page":"251","article-title":"Effect of Heart Rate-Oriented Therapy on Diastolic Functions in Patients with Heart Failure with Reduced Ejection Fraction","volume":"34","author":"Tas","year":"2018","journal-title":"Acta Cardiol. Sin."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1161\/hc1202.105290","article-title":"New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment","volume":"105","author":"Zile","year":"2002","journal-title":"Circulation"},{"key":"ref_34","unstructured":"Novack, M.L., and Zubair, M. (2024). Natriuretic Peptide B Type Test, StatPearls."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0828-282X(06)70908-4","article-title":"Nonheart failure-associated elevation of amino terminal pro-brain natriuretic peptide in the setting of sepsis","volume":"22","author":"Bar","year":"2006","journal-title":"Can. J. Cardiol."},{"key":"ref_36","first-page":"1893","article-title":"The role of BNP testing in heart failure","volume":"74","author":"Doust","year":"2006","journal-title":"Am. Fam. Physician"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.jchf.2020.10.008","article-title":"Unexpectedly Low Natriuretic Peptide Levels in Patients With Heart Failure","volume":"9","author":"Bachmann","year":"2021","journal-title":"JACC Heart Fail."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5218","DOI":"10.1210\/en.2010-0355","article-title":"Decreased expression of natriuretic peptides associated with lipid accumulation in cardiac ventricle of obese mice","volume":"151","author":"Bartels","year":"2010","journal-title":"Endocrinology"},{"key":"ref_39","unstructured":"Fink, G. (2007). Left Ventricular Mass. Encyclopedia of Stress, Academic Press."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12538","DOI":"10.1073\/pnas.1615051113","article-title":"Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase","volume":"113","author":"Chang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bruder-Nascimento, T., Ekeledo, O.J., Anderson, R., Le, H.B., and Belin de Chantemele, E.J. (2017). Long Term High Fat Diet Treatment: An Appropriate Approach to Study the Sex-Specificity of the Autonomic and Cardiovascular Responses to Obesity in Mice. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00032"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1093\/cvr\/cvu154","article-title":"Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in micedagger","volume":"103","author":"Deng","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1172\/JCI77126","article-title":"Energy homeostasis targets chromosomal reconfiguration of the human GH1 locus","volume":"124","author":"Vakili","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"22849","DOI":"10.1074\/jbc.M113.474999","article-title":"CCAAT-enhancer-binding protein beta (C\/EBPbeta) and downstream human placental growth hormone genes are targets for dysregulation in pregnancies complicated by maternal obesity","volume":"288","author":"Vakili","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e13258","DOI":"10.1111\/jne.13258","article-title":"Effect of high fat diet on maternal behavior, brain-derived neurotrophic factor and neural stem cell proliferation in mice expressing human placental lactogen during pregnancy","volume":"36","author":"Moazzam","year":"2023","journal-title":"J. Neuroendocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/dna.2016.3507","article-title":"Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx\/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity","volume":"36","author":"Wang","year":"2017","journal-title":"DNA Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/0844562118786647","article-title":"Univariate Outliers: A Conceptual Overview for the Nurse Researcher","volume":"51","author":"Mowbray","year":"2019","journal-title":"Can. J. Nurs. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/269\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:57:32Z","timestamp":1760115452000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,31]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010269"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010269","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,31]]}}}