Author + information
- Akihiko Kubota,
- Hiroshi Hasegawa,
- Yoshihito Kameda,
- Kobara Yuka,
- Hiroyuki Tadokoro,
- Yoshio Kobayashi,
- Issei Komuro and
- Hiroyuki Takano
Dipeptidyl peptidase-4 (DPP-4) inhibitors are newly available drugs for diabetes mellitus, but it is unclear whether DPP-4 inhibitors have cardioprotective effects or not.
8-week-old C57BL/6 mice fed with high-fat diet (HFD) were injected with a single dose of streptozotocin to induce diabetes (75 mg/kg i.p.). After 4 weeks, mice were subjected to permanent ligation of left coronary artery and randomized to treatment with either HFD alone (control group) or HFD plus DPP-4 inhibitor (MK-626, 3mg/kg/day) (MK group). Left ventricular function was assessed using echocardiography at day 5 after acute myocardial infarction (AMI). Infarct size, the number of vessels, and myocardial ischemia were assessed at day 5. Serum DPP-4 activity was assessed at day 3. The levels of phosphorylated Akt, ERK, STAT-3 and Bcl-2 in the ischemic region of post-MI heart at day 3 were analyzed by western blot analysis.
Serum DPP-4 activity was increased in control group compared to sham group, but it was significantly decreased by DPP-4 inhibitor (sham, 360±93RLU, control, 853±114RLU, MK, 104±78RLU, p<0.05) at 3 days after AMI. The treatment with DPP-4 inhibitor significantly improved left ventricular ejection fraction (sham, 71.2±3.6%, control, 20.8±6.7%, MK, 40.6±4.3%, p<0.05) and decreased the infarction size at 5 days after AMI. DPP-4 inhibitor also increased the ratio of PECAM-positive endothelial cells to dystrophin-positive cardiomyocyte (sham, 0.82±0.03, control, 0.82±0.04, MK, 1.16±0.07, p<0.05) and decreased the area of hypoxyprobe-1-positive myocardial ischemia (sham, 0.26±0.11%, control, 8.71±0.28%, MK, 5.83±0.56%, p<0.05) in the border region at 5 days after AMI. In western blot analysis, the levels of phosphorylated STAT-3 (p-STAT-3) and Bcl-2, but not p-Akt, p-ERK, were significantly increased in MK group compared to control group. These cardioprotective effects were also recognized in DPP-4-/- mice.
DPP-4 inhibitors may have cardioprotective effects on post-MI heart by promoting both survival signaling in cardiomyocytes and angiogenesis.
Poster Sessions, Expo North
Saturday, March 09, 2013, 10:00 a.m.-10:45 a.m.
Session Title: Mechanisms of Metabolic Cardiomyopathy
Abstract Category: 16. Heart Failure: Basic
Presentation Number: 1135-291
- 2013 American College of Cardiology Foundation