Dipeptidyl Peptidase-4 (DPP-4) Inhibition Attenuates Cardiac Dysfunction after Myocardial Infarction Independently of DPP-4

抄録

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. We hypothesized that some beneficial extra-pancreatic effects of DPP-4 inhibitors may be brought in a DPP-4-independent manner. Here, we demonstrated anti-remodeling effect of DPP-4 inhibitors after myocardial infarction (MI) in DPP-4-deficient rats.

Methods: MI was induced by ligation of coronary artery in 8 week-old Fischer 344 rats with inactivating mutation of DPP-4. And they were randomly divided into two groups; a vehicle group and a group treated with 5 mg/kg/day of linagliptin in drinking water. The sham-operated rats were used as a control group. After 4 weeks of treatment, rats underwent echocardiography to assess cardiac function. MI-induced interstitial fibrosis in marginal region of infarction was assessed by Sirius red staining. Interstitial macrophage infiltration was assessed by immunohistochemistorical staining for F4/80. Gene expression levels in marginal area of infarction were quantified by qRT-PCR.

Results: Administration of linagliptin did not affect blood pressure and heart rate, body weight, and infarct size. Left ventricular (LV) systolic function such as ejection fraction was slightly improved by linagliptin. Interestingly, LV diastolic function such as E/E' was significantly improved in the linagliptin group compared with the vehicle group (32.0 ± 4.3 vs 19.0 ± 1.2, respectively). Interstitial fibrosis in marginal region and macrohage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-beta 1 were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. Inflammation-related expressions also tended to be suppressed in the linagliptin group. The inflammation-related and fibrosis-related protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts.

Conclusions: DPP-4 inhibition can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.