Abstract
BackgroundHeart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats.MethodsMale Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days.ResultsBlood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4.ConclusionsVildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats.
Highlights
Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation
The in vivo half-life of Glucagon-like peptide-1 (GLP-1) is very short (2 to 3 min) because it is degraded by dipeptidyl peptidase 4 (DPP4), and DPP4 inhibitors lead to increased GLP-1 levels in the blood and extend the duration of GLP-1 action
Active GLP-1 levels at the fasting state were significantly higher in the isoproterenol + vildagliptin group (ISO-VL) and vehicleVL groups than in the vehicle and ISO groups (Figure 1B), and DPP4 activity at the fasting state was significantly lower in the ISO-VL and vehicle-VL groups than in the vehicle and ISO groups (Figure 1C)
Summary
Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. An experimental study showed that a GLP-1 analog had protective effects on high-fat diet–induced insulin resistance [11], inflammation [12], and myocardial infarction [13]. Recent experimental studies evaluated the protective effect of DPP4 inhibitors in cardiovascular disease in hypertension [14], heart failure [15], and myocardial infarction [16,17,18]
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