Effective Treatment of Diabetic Cardiomyopathy and Heart Failure with Reconstituted HDL (Milano) in Mice

Abstract

The risk of heart failure (HF) is prominently increased in patients with type 2 diabetes mellitus. The objectives of this study were to establish a murine model of diabetic cardiomyopathy induced by feeding a high-sugar/high-fat (HSHF) diet and to evaluate the effect of reconstituted HDL_Milano administration on established HF in this model. The HSHF diet was initiated at the age of 12 weeks and continued for 16 weeks. To investigate the effect of reconstituted HDL_Milano on HF, eight intraperitoneal administrations of MDCO-216 (100 mg/kg protein concentration) or of an identical volume of control buffer were executed with a 48-h interval starting at the age of 28 weeks. The HSHF diet-induced obesity, hyperinsulinemia, and type 2 diabetes mellitus. Diabetic cardiomyopathy was present in HSHF diet mice as evidenced by cardiac hypertrophy, increased interstitial and perivascular fibrosis, and decreased myocardial capillary density. Pressure-volume loop analysis indicated the presence of both systolic and diastolic dysfunction and of decreased cardiac output in HSHF diet mice. Treatment with MDCO-216 reversed pathological remodelling and cardiac dysfunction and normalized wet lung weight, indicating effective treatment of HF. No effect of control buffer injection was observed. In conclusion, reconstituted HDL_Milano reverses HF in type 2 diabetic mice.

Keywords: diabetic cardiomyopathy; obesity; type 2 diabetes mellitus.

Figure 1

Time course of body weight (A) and blood glucose levels (B) in C57BL/6N mice fed the standard chow (SC) diet or the high-sugar/high-fat (HSHF) diet. Plasma insulin (C), free fatty acids (D), and adiponectin (E) levels at 16 weeks after the start of the diet. Week 0 in panels A and B corresponds to the age of 12 weeks, the start of the HSHF diet. All data represent mean ± SEM. (n = 15 for SC diet; n = 20 for HSHF diet).

Figure 2

Schematic representation of the study design.

Figure 3

Total cholesterol (A), non-HDL cholesterol (B), and HDL cholesterol plasma levels (C) and plasma triglyceride levels (D) in female C57BL/6N mice at the time of sacrifice. All data represent means ± SEM (n = 8).

Figure 4

Time course of body weight (A) and blood glucose levels (B) in reference, buffer, and MDCO-216 C57BL/6N mice fed the SC diet or the HSHF diet. Plasma insulin (C), free fatty acids (D), and adiponectin (E) levels at the time of sacrifice. Week 0 in panels A and B corresponds to the age of 12 weeks, the start of the HSHF diet. All data represent mean ± SEM (n = 15 for SC diet groups; n = 20 for HSHF diet groups).

Figure 5

Representative Sirius-red stained heart cross-sections of reference, buffer, and MDCO-216 SC diet and HSHF diet mice. Scale bar represents 1 mm.

Figure 6

Immunohistochemical and histochemical analysis of the myocardium of reference, buffer, and MDCO-216 SC diet and HSHF diet mice. Representative photomicrographs show laminin-stained cardiomyocytes, CD31-positive capillaries, Sirius-red-stained collagen, and 3-nitrotyrosin positive area. Scale bar represents 50 µm.

Figure 7

Lactate pre-exercise (A), distance covered (B), and lactate post-exercise (C) in reference, buffer, and MDCO-216 C57BL/6N mice fed the SC diet or the HSHF diet. All data represent means ± SEM (n = 10).

Figure 8

Plasma TNF-α concentration in the reference buffer, and MDCO-216 C57BL/6N mice fed the SC diet or the HSHF diet. All data represent means ± SEM (n = 10).