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.

Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism

“…We showed that vildagliptin increased phosphorylated eNOS levels in ischemic muscles and that the ability of vildagliptin to enhance revascularization was abrogated in eNOS-KO mice. Consistent with these observations, previous studies have shown that phosphorylation of eNOS in heart tissue was increased in linagliptin-treated Zucker obese rats (31) and that sitagliptin increased eNOS activation in ischemic muscle (13). It was also reported that treatment of GLP-1 regulated eNOS activity in endothelial cells in vitro (28).…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…These small molecular-weight substances inhibit more than 90% of DPP4 activity and can be orally administered. Several studies in animal models support the evidence of DPP4 inhibition in improving endothelial function and blood pressure [158,159]. In isolated aorta rings incubated with DPP4-inhibitor, the relaxant effect of DPP4-inhibitor is GLP-1 independent and results from Akt posphorylation and eNOS activation with a rapid increase in NO levels [160].…”

“…Pharmacological treatment with sitagliptin has been able to enhance the expression of cardioprotective proteins and improve heart functional recovery after I/R injury [162]. It is not clear how these potential benefits may be mediated, but one possibility involves the DPP4 inhibitors ability to modulate innate and adaptative immunity by suppressing the NF-kB signaling downstream TNF and IL-6 [143,159], and by inhibiting the NLRP3 inflammasome, a multiprotein complex involved in caspase-1 activation and downstream maturation of pro-inflammatory cytokines, TLR4 and IL1β in human macrophages [163]. 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 In contrast to the positive effects in animal experiments, the consequences of treatment with DPP4 inhibitors on endothelial functions in humans have not always been consistent.…”

Significance of Vascular Dipeptidyl Peptidase-4 Inhibition on Vascular Protection in Zucker Diabetic Fatty Rats

“…The ZDF rat is an established animal model of diabetes with obesity (16,17). Blood glucose concentrations in all ZDF groups were significantly higher than lean rats prior to drug treatment.…”