linagliptin and Cardiomyopathies

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and -elevated blood pressure accompanying with inhibition of NADPH oxidase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptides-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 ± 4 and 13 ± 3 vs. 42 ± 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 ± 4 and 10 ± 6 vs. 27 ± 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 ± 22 and 286 ± 25 vs. 339 ± 40 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm

Topics: Angiotensin II; Animals; Cardiomyopathies; Fibrosis; Glucagon-Like Peptide 1; Hypertension; Linagliptin; Liraglutide; Mitochondria; NADPH Oxidase 4; Rats; Rats, Sprague-Dawley

Doxorubicin is an anthracycline chemotherapeutic agent that causes cardiomyopathy as a side effect. Here, we aimed to investigate the effects of linagliptin and bisoprolol on the management of doxorubicin-induced cardiomyopathy in rats.. Wistar rats were divided into six groups (n = 8). Group I received saline for 4 weeks; group II received 1 mg/kg bisoprolol for 8 weeks; group III received 3 mg/kg linagliptin for 8 weeks; group IV received 1.25 mg/kg doxorubicin for 4 weeks for the induction of cardiomyopathy; group V received 1.25 mg/kg doxorubicin for 4 weeks plus 1 mg/kg bisoprolol for 8 weeks; and group VI received 1.25 mg/kg doxorubicin for 4 weeks plus 3 mg/kg linagliptin for 8 weeks. Electrocardiography and isometric mechanography were conducted to measure ventricular contractile responses. Myocardial tissue and serum samples were analyzed for oxidative and cardiotoxic markers by ELISA.. Electrocardiography revealed that QRS, QT and Tp intervals were longer in group IV than group I. Doxorubicin caused a significant decrease in ventricular contraction, which was significantly prevented by bisoprolol. Doxorubicin resulted in myocardial fiber disorganization and disruption, but bisoprolol or linagliptin improved this myocardial damage. Glutathione peroxidase was significantly decreased in groups IV and V. Bisoprolol or linagliptin treatment attenuated the significant doxorubicin-mediated increase in malondialdehyde. Doxorubicin and linagliptin provided significant elevations in CK-MB activity and troponin-I levels.. Doxorubicin resulted in pronounced oxidative stress. The beneficial effects of bisoprolol and linagliptin on myocardial functional, histopathological and biochemical changes could be related to the attenuation of oxidative load.

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Antibiotics, Antineoplastic; Bisoprolol; Cardiomyopathies; Doxorubicin; Electrocardiography; Hypoglycemic Agents; Isometric Contraction; Linagliptin; Male; Myocardial Contraction; Rats; Rats, Wistar

Daunorubicin (DAU) downregulates cytokines promoting stem cell migration and homing into the heart, reducing cardiac regeneration after anticancer chemotherapy. Pegfilgrastim (PFIL) protects from DAU-induced neutropenia but its cardioprotective potential remains unclear. We tested whether pegfilgrastim and a dipeptidyl peptidase-4 inhibitor linagliptin, potential enhancers of stem cells migration and homing, would improve DAU-cardiomyopathy.. DAU (7.5 mg/kg, i.v.) was administered to male Wistar rats to induce cardiotoxicity. Pegfilgrastim (100 µg/kg, s.c.) was administered 24h after DAU, and linagliptin was administered orally for 8 weeks (5 mg/kg/day, LINA). Cardiac damage markers (Nppa, Myh6, Myh7, Gp91phox), cytokines (Sdf-1alpha, Mcp-1, Vegf, Hgf, Igf-1), stem cell markers (Cxcr4, Ccr2, Cd34, Cd133, Cd44, Cd105) were determined by qRT-PCR.. Decreased Myh6, elevated Myh7 Nppa, and Gp91phox were not ameliorated by PFIL + LINA. Downregulated expressions of cytokines (Vegf, Sdf-1alpha) and stem cells markers (Cxcr4, Cd34, Cd133, and Cd105) remained decreased after PFIL + LINA. DAU-induced upregulation of Mcp-1, Ccr2 and Cd44 was further potentiated by PFIL + LINA. PFIL + LINA normalised expression of Hgf and Igf-1.. Although PFIL + LINA failed in universal potentiation of stem cells migration and homing, the expression of stem cell markers Ccr2 and Cd44 in the heart potentially increased through the preservation of Hgf, Igf-1 and upregulation of Mcp-1.

Topics: Animals; Biomarkers; Cardiomyopathies; Cell Movement; Chemokine CCL2; Cytokines; Daunorubicin; Filgrastim; Heart; Hepatocyte Growth Factor; Hyaluronan Receptors; Insulin-Like Growth Factor I; Kaplan-Meier Estimate; Linagliptin; Male; Myocardium; Oxidative Stress; Polyethylene Glycols; Rats; Rats, Wistar; Receptors, CCR2; Stem Cells

Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system.. Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks.. WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structural abnormalities. Further, WD upregulated the expression of TRAF3IP2, a cytoplasmic adapter molecule and a regulator of multiple inflammatory mediators. Linagliptin inhibited its expression, activation of its downstream signaling intermediates NF-κB, AP-1 and p38-MAPK, and induction of multiple inflammatory mediators and growth factors that are known to contribute to development and progression of hypertrophy, fibrosis and contractile dysfunction. Linagliptin also inhibited WD-induced collagens I and III expression. Supporting these in vivo observations, linagliptin inhibited aldosterone-mediated MR-dependent oxidative stress, upregulation of TRAF3IP2, proinflammatory cytokine, and growth factor expression, and collagen induction in cultured primary cardiac fibroblasts. More importantly, linagliptin inhibited aldosterone-induced fibroblast activation and migration.. Together, these in vivo and in vitro results suggest that inhibition of DPP-4 activity by linagliptin reverses WD-induced DD, possibly by targeting TRAF3IP2 expression and its downstream inflammatory signaling.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiomyopathies; Cells, Cultured; Diastole; Diet, Western; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Down-Regulation; Female; Fibrosis; Linagliptin; Mice, Inbred C57BL; Myocarditis; Myocardium; NF-kappa B; Nitrosative Stress; Obesity; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Recovery of Function; Signal Transduction; Time Factors; Transcription Factor AP-1; Ventricular Dysfunction, Left; Ventricular Function, Left

Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).. In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.. DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

Topics: Animals; Area Under Curve; Cardiomyopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Gene Expression Regulation; Glomerular Filtration Rate; Glucagon-Like Peptide 1; Heart; Humans; Kidney Failure, Chronic; Linagliptin; Myocardium; Natriuretic Peptide, Brain; Nephrectomy; Piperidines; Purines; Pyrazines; Quinazolines; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sitagliptin Phosphate; Triazoles; Uracil; Uremia