Dipeptidyl peptidase-4 inhibitors as new tools for cardioprotection

Rankovic, Marina; Jeremić, Nevena; Srejović, Ivan; Radonjić, Katarina; Stojanović, Aleksandra; Glisic, Milos; Bolevich, Stefani; Bolevich, Sergey; Jakovljević, Vladimir

doi:10.1007/s10741-020-10005-5

Cited by 7 publications

(9 citation statements)

References 106 publications

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“…Taking into consideration the results of previously published studies in addition to our observations, we may state that lack of DPP4 activity alleviates myocardial infarct size, improves functional recovery of the heart and prevents left ventricular remodelling in diabetic conditions after myocardial ischaemia/reperfusion 37 . Moreover, it's been suggested that DPP4 inhibition may act protectively on myocardial infarct size by via both GLP‐1R‐dependent and GLP‐1R‐independent mechanisms by improving blood supply to the ischaemic areas of myocardium 30 . Additionally, it has been hypothesized that degradation of stromal cell‐derived factor‐1 alpha (SDF‐1 alpha) by DPP 4 contributes to attenuation of ischaemia‐induced cardiac dysfunction 38 .…”

Section: Discussionsupporting

confidence: 81%

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Dipeptidyl peptidase 4 inhibitors attenuate cardiac ischaemia–reperfusion injury in rats with diabetes mellitus type 2

Bradić

Milosavljevic

Bolevich

et al. 2020

Clin Exp Pharma Physio

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The aim of our study was to assess and compare the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, saxagliptin and sitagliptin, on metabolic control of disease and cardiac function in rats with diabetes mellitus type 2 (T2DM). This research would provide novel understanding into the potentially protective effects of DPP4 inhibitors in helping salvage of the heart exposed to ischaemia–reperfusion (I–R) injury. Forty‐eight Wistar albino rats were randomly divided into four groups: CTRL, Control healthy group; T2DM, rats with T2DM; T2DM + Sit, rats with T2DM treated with 0.6 mg/kg of sitagliptin; T2DM + Sax, rats with T2DM treated with 0.45 mg/kg of saxagliptin for 3 weeks. At the end of the protocol, in vivo cardiac function was assessed by echocardiography, while in the blood samples glucose and insulin were determined. Additionally, ex vivo heart function was estimated on a model of I–R injury using Langendorff apparatus. Immunohistochemical analysis was used to determine the degree of myocardial apoptosis and necrosis, while DPP4 staining was performed to assess the cardiac DPP4 expression. Data were analyzed using a one‐way analysis of variance (ANOVA) and the post hoc Bonferroni test for multiple comparisons. Improved glycoregulation was noticed in rats that received DPP4 inhibitors compared to untreated diabetic rats (P < .05). Moreover, better in vivo systolic function was observed in rats treated with both DPP4 inhibitors as evidenced by an increase in fractional shortening when compared to T2DM (P < .05). Most parameters of cardiac function in treated rats remained unaltered during reperfusion, thus suggesting that both drugs protected myocardium during flow restoration. Better effects on coronary circulation were achieved after sitagliptin application. Additionally, both DPP4 inhibitors showed similar potential to attenuate cardiac necrosis and apoptosis. Saxagliptin and sitagliptin might be efficient in preserving myocardial function and morphology in ex vivo induced I‐R cardiac injury in rats with T2DM.

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Section: Discussionsupporting

confidence: 81%

“…Numerous data support the fact that apoptosis is initiated by reperfusion and plays an important role in structural deterioration of myocardium after ischaemia 30 . In that sense, we aimed to assess if saxagliptin and sitagliptin might affect apoptosis by Bcl‐2 and Tunel staining.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase 4 inhibitors attenuate cardiac ischaemia–reperfusion injury in rats with diabetes mellitus type 2

Bradić

Milosavljevic

Bolevich

et al. 2020

Clin Exp Pharma Physio

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“…Previous works show the inhibition of the senescence pathway in vascular smooth muscle cells appears to affect atherosclerotic plaque vulnerability [ 37–39 ]. DPP-4 inhibitors have shown many beneficial effects in cardiovascular diseases [ 40 , 41 ]. It is possible that this class of drug could have a role in alleviating vascular smooth muscle cells senescence in hyperlipidemia conditions.…”

Section: Discussionmentioning

confidence: 99%

Anagliptin prevented interleukin 1β (IL-1β)-induced cellular senescence in vascular smooth muscle cells through increasing the expression of sirtuin1 (SIRT1)

Zhao¹,

He²,

Zuo³

et al. 2021

Bioengineered

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Vascular smooth muscle cell senescence plays a pivotal role in the pathogenesis of atherosclerosis. Anagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of hyperglycemia. Recent progress indicates that DPP-4 inhibitors show a wide range of cardiovascular benefits. We hypothesize that Anagliptin plays a role in vascular smooth muscle cell senescence and this may imply its modulation of atherosclerosis. Here, the beneficial effect of Anagliptin against interleukin 1β (IL-1β)-induced cell senescence in vascular smooth muscle cells was studied to learn the promising therapeutic capacity of Anagliptin on atherosclerosis. Firstly, we found that Anagliptin treatment ameliorated the elevated secretions of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and macrophage chemoattractant protein-1 (MCP-1). Secondly, our findings indicate that exposure to IL-1β reduced telomerase activity from 26.7 IU/L to 15.8 IU/L, which was increased to 20.3 and 24.6 IU/L by 2.5 and 5 μM Anagliptin, respectively. In contrast, IL-1β stimulation increased senescence-associated β-galactosidase (SA-β-gal) staining to 3.1-fold compared to the control group, it was then reduced to 2.3-and 1.6-fold by Anagliptin dosedependently. Thirdly, Anagliptin dramatically reversed the upregulated p16, p21, and downregulated sirtuin1 (SIRT1) in IL-1β-treated vascular smooth muscle cells. Lastly, the protective effect of Anagliptin against cellular senescence in vascular smooth muscle cells was abolished by silencing of SIRT1. In conclusion, Anagliptin protects vascular smooth muscle cells from cytokine-induced senescence, and the action of Anagliptin in vascular smooth muscle cells requires SIRT1 expression.

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“…In line with this trend, the potential of dipeptidyl peptidase-4 (DPP-4) inhibitors is investigated and discovered. These are well-known antidiabetic drugs that have recently been shown to ameliorate IR damage in organs [ 10 , 11 , 12 , 13 , 14 ]. The rationale is that DPP-4 is involved in the metabolism of many bioactive peptides that act as chemokines, hormones and neuromodulators [ 15 , 16 ] and DPP-4 inhibitors have been shown to display cytoprotective properties, also via DPP4-independent mechanisms [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion

et al. 2021

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A possibility of repurposing sitagliptin, a well-established antidiabetic drug, for alleviating injury caused by ischemia-reperfusion (IR) is being researched. The aim of this study was to shed some light on the molecular background of the protective activity of sitagliptin during hepatic IR. The expression and/or concentration of inflammation and oxidative stress-involved factors have been determined in rat liver homogenates using quantitative RT-PCR and Luminex® xMAP® technology and markers of nitrative and halogenative stress were quantified using targeted metabolomics (LC-MS/MS). Animals (n = 36) divided into four groups were treated with sitagliptin (5 mg/kg) (S and SIR) or saline solution (C and IR), and the livers from IR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). The midkine expression (by 2.2-fold) and the free 3-nitrotyrosine (by 2.5-fold) and IL-10 (by 2-fold) concentration were significantly higher and the Nox4 expression was lower (by 9.4-fold) in the IR than the C animals. As compared to IR, the SIR animals had a lower expression of interleukin-6 (by 4.2-fold) and midkine (by 2-fold), a lower concentration of 3-nitrotyrosine (by 2.5-fold) and a higher Nox4 (by 2.9-fold) and 3-bromotyrosine (by 1.4-fold). In conclusion, IR disturbs the oxidative, nitrative and halogenative balance and aggravates the inflammatory response in the liver, which can be attenuated by low doses of sitagliptin.

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Dipeptidyl peptidase-4 inhibitors as new tools for cardioprotection

Cited by 7 publications

References 106 publications

Dipeptidyl peptidase 4 inhibitors attenuate cardiac ischaemia–reperfusion injury in rats with diabetes mellitus type 2

Dipeptidyl peptidase 4 inhibitors attenuate cardiac ischaemia–reperfusion injury in rats with diabetes mellitus type 2

Anagliptin prevented interleukin 1β (IL-1β)-induced cellular senescence in vascular smooth muscle cells through increasing the expression of sirtuin1 (SIRT1)

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion

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