Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Aroor, Annayya R.; Sowers, James R.; Jia, Guanghong; DeMarco, Vincent G.

doi:10.1152/ajpheart.00209.2014

Cited by 97 publications

(108 citation statements)

References 208 publications

(282 reference statements)

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“…Thus, we believe that antihypertensive effect of linagliptin may be derived from reversing IL-6 upregulation in doxorubicin nephropathy. Besides, the antihypertensive action of linagliptin can be explained by its reported ability to upregulate endothelial nitric oxide synthase (eNOS) and restore endothelium-dependent vasodilation [48,49].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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Background/Aims: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. Methods: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. Results: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91^phox, p47^phox, and p67^phox in rat kidneys with doxorubicin nephropathy. Conclusion: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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“…SDF‐1α and B‐type natriuretic peptide are regarded as important substrates of DPP‐4, inactivated by DPP‐4. As a result, they are supposed to mediate favorable effects of DPP‐4 inhibitors on CVD. DPP‐4 inhibition around acute ischemic injury, such as hind limb ischemia and cardiac ischemia/reperfusion in animal models, has consistently enhanced recruitment of SDF‐1α and endothelial progenitor cells in the damaged tissue, promoting tissue regeneration.…”

Section: Discussionmentioning

confidence: 99%

Vildagliptin reduces plasma stromal cell‐derived factor‐1α in patients with type 2 diabetes compared with glimepiride

Park

Kwak

Cho

et al. 2016

J of Diabetes Invest

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Aims/IntroductionDipeptidyl peptidase‐4 inhibitors might have pleiotropic protective effects on cardiovascular disease (CVD), in contrast to sulfonylureas. Therefore, we compared various CVD risk factors between vildagliptin and glimepiride.Materials and MethodsWe carried out a randomized, prospective and crossover trial. A total of 16 patients with type 2 diabetes whose glycated hemoglobin was >7% were randomized to add vildagliptin or glimepiride. After 12‐week treatment, each drug was replaced with the other for another 12 weeks. Before and after each treatment, glucose homeostasis and CVD risk factors were assessed, and the continuous glucose monitoring system was applied to calculate glycemic variability.ResultsThe mean age of the participants was 60 years, 31% were men, body mass index 25.5 kg/m2 and HbA1c 8.41%. Both vildagliptin and glimepiride significantly decreased glycated hemoglobin and glycemic variability indices. Despite the improved glucose homeostasis, favorable change of CVD markers was not prominent in both the arms, along with significant weight gain. Only plasma stromal cell‐derived factor (SDF)‐1α decreased by 30% in the vildagliptin arm. According to regression analyses, the reduction of SDF‐1α was independently associated with vildagliptin usage and serum interleukin‐6 changes, but white blood cells were not related with the SDF‐1α changes.ConclusionCompared with glimepiride, vildagliptin arrestingly decreased plasma SDF‐1α, and its clinical implications should be further investigated.

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“…Emerging evidence suggests that DPPIV inhibitors, also known as gliptins, may provide cardiovascular benefits beyond glycemic control (1,3,4,13,23,40). In fact, genetic deletion or pharmacological inhibition of DPPIV improves cardiovascular outcomes after myocardial infarction in both normoglycemic and diabetic mice (42).…”

Section: This Study Shows That Dipeptidyl Peptidase IV (Dppiv) Inhibimentioning

confidence: 99%

The contributions of dipeptidyl peptidase IV to inflammation in heart failure

Salles

Zogbi

Lima

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Circulating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-α, IL-1β, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.

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Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Cited by 97 publications

References 208 publications

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Vildagliptin reduces plasma stromal cell‐derived factor‐1α in patients with type 2 diabetes compared with glimepiride

The contributions of dipeptidyl peptidase IV to inflammation in heart failure

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