Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Abstract

Background: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. Methods: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. Results: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e′ ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (− dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. Conclusions: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

Endogenous asymmetric dimethylarginine accumulation contributes to the suppression of myocardial mitochondrial biogenesis in type 2 diabetic rats

“…Although the pathogenesis of DCM is not completely understood, emerging evidence demonstrate that mitochondrial dysfunction plays an essential role in the development of DCM [2,3]. Zhang X et al recently reported that treatment of diabetic rabbits with dipeptidyl peptidase-4 inhibitor could prevent cardiac dysfunction, either preserve myocardial mitochondrial function or improve mitochondrial biosynthesis [31]. The present study demonstrated the suppressed mitochondrial biogenesis, impaired mitochondrial function, and increased oxidative stress in the myocardium of T2DM rats.…”

The Relationship Between Plasma DPP4 Activity to BDNF Ratio and Mild Cognitive Impairment in Elderly Population With Normal Glucose Tolerance

“…Accumulated basic and clinical evidence have demonstrated that DPP4 dose-dependently increased oxidative stress production (Ishibashi et al, 2013; Zheng et al, 2015b). More importantly, previous studies have proved that DPP4 inhibitors, such as Alogliptin or Vildagliptin, suppressed oxidative stress in different animal models (Abdelsalam and Safar, 2015; Yisireyili et al, 2016; Aroor et al, 2017; Zhang et al, 2018). With regard to the association between oxidative stress and BDNF, oxidative stress has been proven to cause a decrease in BDNF expression in basic research, while the underlying mechanisms was partly attributed to the impairment of N-methyl- D -aspartate channel (Wu et al, 2004).…”

Mitochondrial dysfunction in fibrotic diseases

“…Mitoquinone (MitoQ), a mitochondrial-targeted antioxidant, could inhibit fibrosis in pressure overloaded hearts via targeting mitochondrial ROS-mediated signaling TGF-β1, NADPH oxidase 4 (NOX4), and Nrf2 pathway 47 . Bendavia and alogliptin could improve mitochondrial dysfunction, relieved cardiac fibrosis by improving mitochondrial biogenesis 48,49 .…”

“…Mitochondrial membrane potential and membrane structural damage are also important characteristics in cardiac fibrosis. It is reported that alogliptin alleviated interstitial fibrosis in diabetic rabbits by reducing the production of mitochondrial ROS, preventing the mitochondrial membrane depolarization, and improving the swelling of mitochondria 49 . Similarly, melatonin and ephedrine-4 could alleviate oxidative stress and cardiac fibrosis through maintaining the integrity of mitochondrial membrane and preventing the release of cytochrome C 53 .…”

“…Improving mitochondrial biogenesis by PGC-1α/NRF1/Tfam pathway. 49 Heart/cardiorenal syndrome Melatonin and ephedrine-4 Alleviating oxidative stress, maintaining the integrity of mitochondrial membrane and preventing the release of cytochrome C 53 Heart/heart failure Mitoquinone (a mitochondrial-targeted antioxidant) 1. Inhibiting TGF-β1 and NOX4 expression; 2.…”