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Heart failure with preserved ejection fraction (HFpEF) is a poorly understood cardiovascular complication of diabetes mellitus (DM). Little is known about whether EXO-miRNAs can be used as biomarkers for HFpEF in DM. We aimed to investigate the relationship between EXO-miRNAs and HFpEF in STZ-induced diabetic rats. We prepared STZ-induced diabetic rats exhibiting a type 1 DM phenotype with low body weight, hyperglycemia, hyperlipidemia and hypoinsulinemia. Histological sections confirmed atrophy and fibrosis of the heart, with collagen accumulation representing diabetic cardiomyopathy. Significant decreases in end-diastolic volume, stroke volume, stroke work, end-systolic elastance and cardiac output indicated impaired cardiac contractility, as well as mRNA conversion of two isoforms of myosin heavy chain (\u03b1-MHC and \u03b2-MHC) and increased atrial natriuretic factor (ANF) mRNA indicating heart failure, were consistent with the features of HFpEF. In diabetic HFpEF rats, we examined a selected panel of 12 circulating miRNAs associated with HF (miR-1-3p, miR-21-5p, miR-29a-5p, miR-30d-5p, miR-34a-5p, miR-126a-5p, miR-143-3p, miR-145-5p, miR-195-5p, miR-206-3p, miR-320-3p and miR-378-3p). Although they were all expressed at significantly lower levels in the heart compared to non-diabetic controls, only six miRNAs (miR-21-5p, miR-30d-5p, miR-126a-5p, miR-206-3p, miR-320-3p and miR-378-3p) were also reduced in exosomal content, while one miRNA (miR-34a-5p) was upregulated. Similarly, although all miRNAs were correlated with reduced cardiac output as a measure of cardiovascular performance, only three miRNAs (miR-30d-5p, miR-126a-5p and miR-378-3p) were correlated in exosomal content. We found that miR-30d-5p and miR-126a-5p remained consistently correlated with significant reductions in exosomal expression, cardiac expression and cardiac output. Our findings support their release from the heart and association with diabetic HFpEF. We propose that these two EXO-miRNAs may be important for the development of diagnostic tools for diabetic HFpEF.<\/jats:p>","DOI":"10.3390\/ijms23147514","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T09:41:10Z","timestamp":1657100470000},"page":"7514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Exosomal microRNAs miR-30d-5p and miR-126a-5p Are Associated with Heart Failure with Preserved Ejection Fraction in STZ-Induced Type 1 Diabetic Rats"],"prefix":"10.3390","volume":"23","author":[{"given":"Jiung-Pang","family":"Huang","sequence":"first","affiliation":[{"name":"Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4377-7026","authenticated-orcid":false,"given":"Chih-Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei 220, Taiwan"},{"name":"Graduate Institute of Clinical Medicine Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, Yilan 266, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuang-Jing","family":"Huang","sequence":"additional","affiliation":[{"name":"Microscopy Center, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne M.","family":"Sokal","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hsing","family":"Chen","sequence":"additional","affiliation":[{"name":"Kidney Research Center, Chang Gung Memorial Hospital, Linkou 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Man","family":"Hung","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Kidney Research Center, Chang Gung Memorial Hospital, Linkou 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12933-021-01242-5","article-title":"Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort","volume":"20","author":"Lejeune","year":"2021","journal-title":"Cardiovasc. 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