{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T22:26:11Z","timestamp":1785882371906,"version":"3.56.0"},"reference-count":61,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T00:00:00Z","timestamp":1557100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fonds voor Wetenschappelijk Onderzoek-Vlaanderen","award":["G0A3114N"],"award-info":[{"award-number":["G0A3114N"]}]},{"name":"Onderzoekstoelagen grant KU Leuven","award":["OT\/13\/090"],"award-info":[{"award-number":["OT\/13\/090"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypercholesterolemia may be causally related to heart failure with preserved ejection fraction (HFpEF). We aimed to establish a HFpEF model associated with hypercholesterolemia and type 2 diabetes mellitus by feeding a high-sucrose\/high-fat (HSHF) diet to C57BL\/6J low-density lipoprotein receptor (LDLr)\u2212\/\u2212 mice. Secondly, we evaluated whether cholesterol-lowering adeno-associated viral serotype 8 (AAV8)-mediated LDLr gene transfer prevents HFpEF. AAV8-LDLr gene transfer strongly (p &lt; 0.001) decreased plasma cholesterol in standard chow (SC) mice (66.8 \u00b1 2.5 mg\/dl versus 213 \u00b1 12 mg\/dl) and in HSHF mice (84.6 \u00b1 4.4 mg\/dl versus 464 \u00b1 25 mg\/dl). The HSHF diet induced cardiac hypertrophy and pathological remodeling, which were potently counteracted by AAV8-LDLr gene transfer. Wet lung weight was 19.0% (p &lt; 0.001) higher in AAV8-null HSHF mice than in AAV8-null SC mice, whereas lung weight was normal in AAV8-LDLr HSHF mice. Pressure\u2013volume loop analysis was consistent with HFpEF in AAV8-null HSHF mice and showed a completely normal cardiac function in AAV8-LDLr HSHF mice. Treadmill exercise testing demonstrated reduced exercise capacity in AAV8-null HSHF mice but a normal capacity in AAV8-LDLr HSHF mice. Reduced oxidative stress and decreased levels of tumor necrosis factor-\u03b1 may mediate the beneficial effects of cholesterol lowering. In conclusion, AAV8-LDLr gene therapy prevents HFpEF.<\/jats:p>","DOI":"10.3390\/ijms20092222","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T08:19:59Z","timestamp":1557389999000},"page":"2222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cholesterol-Lowering Gene Therapy Prevents Heart Failure with Preserved Ejection Fraction in Obese Type 2 Diabetic Mice"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-6620","authenticated-orcid":false,"given":"Joseph Pierre","family":"Aboumsallem","sequence":"first","affiliation":[{"name":"Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3550-7672","authenticated-orcid":false,"given":"Ilayaraja","family":"Muthuramu","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mudit","family":"Mishra","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5580-686X","authenticated-orcid":false,"given":"Bart","family":"De Geest","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1001\/jama.1979.03290450033020","article-title":"Diabetes and cardiovascular disease. 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