A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4.

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. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats. After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg-1·day-1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage 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-β1 (TGF-β1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-β1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts. Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.

Yamaguchi T ，Watanabe A ，Tanaka M ，Shiota M ，Osada-Oka M ，Sano S ，Yoshiyama M ，Miura K ，Kitajima S ，Matsunaga S ，Tomita S ，Iwao H ，Izumi Y ... -  《-》

Dipeptidyl peptidase-4 inhibitor improves cardiac function by attenuating adverse cardiac remodelling in rats with chronic myocardial infarction.

What is the central question of this study? Although cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated, their cardiac effects in chronic myocardial infarction (MI) are unclear. We determined the effects of a DPP-4 inhibitor on cardiac function and remodelling in rats with chronic MI. What is the main finding and its importance? We demonstrated, for the first time, that DPP-4 inhibitor, but not metformin, exerted similar efficacy in improving cardiac function and attenuating cardiac fibrosis compared with enalapril in rats with chronic MI. These findings reveal benefits additional to the glycaemic control by the DPP-4 inhibitor in chronic MI, and it might become the new drug of choice for MI in patients with diabetes mellitus. Adverse cardiac remodelling after myocardial infarction (MI) leads to progressive heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new antidiabetic drugs that exert cardioprotection. However, their role in cardiac function and remodelling in chronic MI is unclear. We hypothesized that the DPP-4 inhibitor vildagliptin reduces adverse cardiac remodelling and improves cardiac function in rats with chronic MI. These effects were also compared with enalapril and metformin. Male Wistar rats (n = 36) with chronic MI induced by ligation of the left anterior descending coronary artery were divided into six groups to receive vehicle, vildagliptin (3 mg kg(-1)  day(-1) ), metformin (30 mg kg(-1)  day(-1) ), enalapril (10 mg kg(-1)  day(-1) ), combined metformin and enalapril or combined vildagliptin and enalapril for 8 weeks. At the end of the study, plasma malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, pathological and biochemical studies of cardiac remodelling were investigated. Our study demonstrated that rats with chronic MI had increased oxidative stress levels, depressed HRV, adverse cardiac remodelling, indicated by cardiac fibrosis, and LV dysfunction. Treatment with vildagliptin or enalapril significantly decreased oxidative stress, attenuated cardiac fibrosis and improved HRV and LV function. We conclude that vildagliptin exerts similar cardioprotective effects to enalapril in attenuating oxidative stress and cardiac fibrosis and improving cardiac function in rats with chronic MI. Metformin does not provide these benefits in this model. Moreover, addition of either metformin or vildagliptin to enalapril does not provide additional benefit in attenuating cardiac remodelling or improving LV function compared with enalapril alone.

Inthachai T ，Lekawanvijit S ，Kumfu S ，Apaijai N ，Pongkan W ，Chattipakorn SC ，Chattipakorn N ... -  《-》

Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together.

Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.

Wang X ，Ding Z ，Yang F ，Dai Y ，Chen P ，Theus S ，Singh S ，Budhiraja M ，Mehta JL ... -  《-》

Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice.

Aroor AR ，Habibi J ，Kandikattu HK ，Garro-Kacher M ，Barron B ，Chen D ，Hayden MR ，Whaley-Connell A ，Bender SB ，Klein T ，Padilla J ，Sowers JR ，Chandrasekar B ，DeMarco VG ... -  《-》

Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy.

Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin β4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-β1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin β4 and TGF-β1) influenced by DPP-4 inhibition.

Hasan AA ，von Websky K ，Reichetzeder C ，Tsuprykov O ，Gaballa MMS ，Guo J ，Zeng S ，Delić D ，Tammen H ，Klein T ，Kleuser B ，Hocher B ... -  《-》