期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/ijms20092222
关键词
gene therapy; heart failure with preserved ejection fraction; type 2 diabetes; oxidative stress; hypercholesterolemia
资金
- Onderzoekstoelagen grant of the KU Leuven [OT/13/090]
- Fonds voorWetenschappelijk Onderzoek-Vlaanderen [G0A3114N]
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)(-/-) 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 < 0.001) decreased plasma cholesterol in standard chow (SC) mice (66.8 +/- 2.5 mg/dl versus 213 +/- 12 mg/dl) and in HSHF mice (84.6 +/- 4.4 mg/dl versus 464 +/- 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 < 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-volume 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- may mediate the beneficial effects of cholesterol lowering. In conclusion, AAV8-LDLr gene therapy prevents HFpEF.
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