Abstract
Introduction: Diabetes mellitus (DM) is a main risk factor for diastolic dysfunction (DD), the underlying pathological condition of heart failure with preserved ejection fraction (HFpEF). Nevertheless, the mechanism linking DM and DD is unclear. DM causes a low level inflammatory response, and we tested whether macrophage-dependent IL-1β secretion was the cause of DM-associated DD. Methods: Type II diabetic mice were induced by feeding 60% kcal high fat diet (HFD) for at least 20 weeks. Cardiac macrophage accumulation was assessed by flow cytometry. Diabetic mice were subjected to IL-1β suppressing treatment with IL-1 receptor antagonist (IL-1RA) or macrophage depletion by Clodronate liposome, and mouse cardiac diastolic function was evaluated by echocardiogram (E/E’). To determine the role of macrophage-dependent IL-1β in the DD development, fatty acid binding protein 4 knockout (FABP4 KO) mice were employed, and the secretory profile of isolated macrophages was examined by microarray and ELISA. The relation between IL-1β and the cardiac mitochondrial oxidative stress was investigated to explore the potential mechanism of IL-1β mediated DD. Results: Diabetic mice presented DD (E/E’, 19.6 ± 0.8 in control vs. 26.8 ± 0.8 in DM, p<0.05), higher IL-1β level (3.7 ± 0.6 pg/ml in control vs. 9.1 ± 0.8 pg/ml in DM, p<0.05), and increased macrophage accumulation in the hearts (F/80 + cells, 15.7 ± 0.8% in control vs. 19.6 ± 1.3% in DM, p<0.05). DD was significantly ameliorated by suppressing IL-1β (E/E’, 22.2 ± 1.5, p<0.05 vs. control) or depleting macrophages (E/E’, 15.8 ± 0.7, p<0.05 vs control) in DM mice. Confirming the central role of macrophages and IL-1β, mice with fatty acid binding protein 4 knockout (FABP4 KO) were unable to secrete IL-1β and were resistant to diabetes-induced DD (E/E’, 17.2 ± 1.3 in KO+HFD vs. 22.1 ± 1.1 in wildtype+HFD, p<0.05). IL-1β regulated the mitoROS generation in cardiomyocytes, and a mitochondrially targeted antioxidant (mitoTempo) prevent diabetic-associated DD (E/E’, 20.7 ± 1.6, p<0.05 vs. control). Conclusions: DM-associated DD was mediated by macrophage-dependent IL-1β secretion. MitoROS provided a mechanistic link between macrophage secreted IL-1β and diabetic DD.
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