title: Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats.
abstract: Diastolic dysfunction is a prognosticator for future cardiovascular events that demonstrates a strong correlation with obesity. Pharmacological inhibition of dipeptidylpeptidase-4 (DPP-4) to increase the bioavailability of glucagon-like peptide-1 is an emerging therapy for control of glycemia in type 2 diabetes patients. Accumulating evidence suggests that glucagon-like peptide-1 has insulin-independent actions in cardiovascular tissue. However, it is not known whether DPP-4 inhibition improves obesity-related diastolic dysfunction. Eight-week-old Zucker obese (ZO) and Zucker lean rats were fed normal chow diet or diet containing the DPP-4 inhibitor, linagliptin (LGT), for 8 weeks. Plasma DPP-4 activity was 3.3-fold higher in ZO compared with Zucker lean rats and was reduced by 95% with LGT treatment. LGT improved echocardiographic and pressure volume-derived indices of diastolic function that were impaired in ZO control rats, without altering food intake or body weight gain during the study period. LGT also blunted elevated blood pressure progression in ZO rats involving improved skeletal muscle arteriolar function, without reducing left ventricular hypertrophy, fibrosis, or oxidative stress in ZO hearts. Expression of phosphorylated- endothelial nitric oxide synthase (eNOS)(Ser1177), total eNOS, and sarcoplasmic reticulum calcium ATPase 2a protein was elevated in the LGT-treated ZO heart, suggesting improved Ca(2+) handling. The ZO myocardium had an abnormal mitochondrial sarcomeric arrangement and cristae structure that were normalized by LGT. These studies suggest that LGT reduces blood pressure and improves intracellular Cai(2+) mishandling and cardiomyocyte ultrastructure, which collectively result in improvements in diastolic function in the absence of reductions in left ventricular hypertrophy, fibrosis, or oxidative stress in insulin-resistant ZO rats.
authors: Department of Internal Medicine, University of Missouri School of Medicine, and Diabetes and Cardiovascular Center, Columbia, MO 65212, USA.
authors: Annayya R
authors: AR
authors: Aroor
authors: James R
authors: JR
authors: Sowers
authors: Shawn B
authors: SB
authors: Bender
authors: Ravi
authors: R
authors: Nistala
authors: Mona
authors: M
authors: Garro
authors: Irina
authors: I
authors: Mugerfeld
authors: Melvin R
authors: MR
authors: Hayden
authors: Megan S
authors: MS
authors: Johnson
authors: Muhammad
authors: M
authors: Salam
authors: Adam
authors: A
authors: Whaley-Connell
authors: Vincent G
authors: VG
authors: Demarco
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology*; D000069476:Linagliptin; D008297:Male; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D052250:Nitric Oxide Synthase Type III; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
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