GIP advanced cardiac remodeling after LAD ligation leading to improved left-ventricular function

Introduction:

DPP-4 inhibitors are used to treat Diabetes, exerting their actions through prolonging the half-life of the incretin hormones GIP and GLP1. In addition, they were found to have cardioprotective effects, leading to reduced size of myocardial infarction and improved left ventricular function in experimental models. These effects have mainly been attributed to GLP1, while the relevance of GIP remains unexplored. In this study we aimed to investigate the functional relevance of GIP during myocardial infarction in mice.

Methods and results:

An adeno-associated viral vector system was used to overexpress GIP in comparison to LacZ (control) in 6 week old C57BL/6J mice (n = 16/group) on normal chow diet. This led to a 17-fold increase of circulating GIP levels. Myocardial infarction was induced by permanent LAD ligation in comparison to Sham procedure. GIP treatment significantly improved cardiac contractility 4 weeks after LAD ligation by millar catheter (dp/dt_max: 12034 mmHg/s [GIP] vs. 8588 mmHg/s [cont.] p < 0.05 with dobutamin stress). This was not attributable to a change in myocardial infarction size (41% [GIP] vs. 35% [LacZ] P = 0,42), but to a significant reduction of interstitial cardiac fibrosis of not-infarcted tissue (1,3% [GIP] vs. 11,6% [LacZ] P < 0,01), with reduction of type III collagen (0,56% [GIP] vs. 1,40% [LacZ] P < 0,05). On a molecular level GIP increased ERK activation as a downstream target of the GIP-Receptor and reduced JNK-activation as a profibrotic signal.

Conclusion:

Chronic GIP treatment improves left ventricular contractility and reduces interstitial cardiac fibrosis following permanent LAD ligation, while not affecting the size of myocardial infarction.