Dipeptidyl peptidase-4 inhibitor reduces infarct size and preserves cardiac function via mitochondrial protection in ischaemia–reperfusion rat heart

Chinda, Kroekkiat; Sanit, Jantira; Chattipakorn, Nipon

doi:10.1177/1479164113516134

Cited by 59 publications

(78 citation statements)

References 49 publications

(77 reference statements)

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“…These treatments also decreased cardiomyocyte apoptosis and thus limited the size of myocardial infarction. According to previous studies, both estrogen and vildagliptin have been reported as protecting the cellular redox balance343536. Treatment with estrogen has been shown to upregulate the level and activity of anti-oxidant enzymes (i.e.…”

Section: Discussionmentioning

confidence: 99%

DPP-4 Inhibitor and Estrogen Share Similar Efficacy Against Cardiac Ischemic-Reperfusion Injury in Obese-Insulin Resistant and Estrogen-Deprived Female Rats

Sivasinprasasn

Tanajak

Pongkan

et al. 2017

Sci Rep

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Estrogen deprivation aggravates cardiac injury after myocardial ischemia and reperfusion (I/R) injury. Although either estrogen or the dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, reduces myocardial damage following cardiac I/R, their effects on the heart in obese-insulin resistant and estrogen deprived conditions remain unknown. Ovariectomized (O) rats (n = 36) were divided to receive either normal diet (NDO) or high-fat diet (HFO) for 12 weeks, followed by treatment with a vehicle, estrogen or vildagliptin for 4 weeks. The setting of in vivo cardiac I/R injury, 30-min ischemia and 120-min reperfusion, was performed. At 12 weeks after ovariectomy, both NDO and HFO rats exhibited an obese-insulin resistant condition. Both NDO and HFO rats treated with estrogen and vildagliptin showed reduced fasting plasma glucose, insulin and HOMA index. Both treatments improved cardiac function indicated by restoration of heart rate variability and increased %left ventricular ejection fraction (%LVEF). The treatments similarly protected cardiac mitochondrial function against I/R injury, leading to a reduction in the infarct size, oxidative stress and apoptosis in the ischemic myocardium. These findings demonstrate that vildagliptin effectively improves metabolic status, and shares similar efficacy to estrogen in reducing myocardial infarction and protecting cardiac mitochondrial function against I/R injury in estrogen-deprived obese-insulin resistant rats.

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Section: Discussionmentioning

confidence: 99%

DPP-4 Inhibitor and Estrogen Share Similar Efficacy Against Cardiac Ischemic-Reperfusion Injury in Obese-Insulin Resistant and Estrogen-Deprived Female Rats

Sivasinprasasn

Tanajak

Pongkan

et al. 2017

Sci Rep

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“…At the end of 3 and 4 months of the experiment, all rat groups had their cardiac function determined by echocardiography. After 4 months of the experimental period, half of the rats in each group (n = 6/group) were deeply anesthetized by intraperitoneal injections of Zolitil (ZolazepamTiletamine) 50 mg/kg combined with Xylazine 3 mg/kg70, then the hearts were rapidly removed. The heart tissues were frozen in liquid nitrogen immediately, and stored at −80 °C in preparation for western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

Wongjaikam

Kumfu

Khamseekaew

et al. 2017

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Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.

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“…24 Animal studies showed that DPP4i improved LV function and reduced ischaemic reperfusion injury in the setting of acute coronary syndrome. 8 In an obese diabetic mice model, inhibition of DPP4 decreased LV stiffness and improved global LV performance. 25 However, concerns regarding the safety of DPP4i were raised following the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI) study, which found that the rate of hospitalization for heart failure was greater in patients receiving saxagliptin.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple potentially beneficial effects have been demonstrated in patients with T2DM. These include reduction of cardiovascular risk, 4 blood pressure 5 and cholesterol lowering, 6 protective effects on endothelial function, 7 improvements in LV contractile performance and reduction in ischaemic/reperfusion injury in the setting of myocardial infarction in animals 8 and humans, 9 as well as anti-inflammatory 10 and anti-fibrotic effects. 11 A recent study by Nogueira et al 12 demonstrated improvements in LV diastolic function in patients with T2DM randomized to sitagliptin versus insulin as add-on therapy to metformin and glyburide.…”

Section: Introductionmentioning

confidence: 99%

Effects of dipeptidyl peptidase-4 inhibitors on cardiac and endothelial function in type 2 diabetes mellitus: A pilot study

Leung

Wong

2016

Diabetes and Vascular Disease Research

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Aims: Recent studies have raised concerns regarding increased heart failure in patients on dipeptidyl peptidase-4 inhibitors. We examined whether dipeptidyl peptidase-4 inhibitors, compared to non-incretin-based therapies, have differential effects on left ventricular and endothelial function in patients with type 2 diabetes mellitus. Methods: A total of 25 type 2 diabetes mellitus patients commenced on a dipeptidyl peptidase-4 inhibitor were compared with 50 matched controls. Left ventricular systolic and diastolic function and flow-mediated dilatation were compared before and 12 months after treatment. Results: At baseline, both dipeptidyl peptidase-4 inhibitor and control groups had elevated HbA 1c and comparable subclinical left ventricular dysfunction (left ventricular global longitudinal strain: −15.4% vs −15.9%, p = 0.538; e′ velocities: 6 vs 6 cm/s, p = 0.151, where e′ is the peak mitral annular early diastolic tissue velocity). After 12 months, both groups had similar improvement in HbA 1c . However, patients on dipeptidyl peptidase-4 inhibitors had greater improvement in systolic (ΔGLS: 3.6% vs 1.3%, p < 0.001), despite no significant differences in weight, blood pressure or lipid parameters in both groups. Diastolic (Δe′: 38% vs 17%, p = 0.001) and endothelial function improved in the dipeptidyl peptidase-4 inhibitor group but not the control group (ΔFMD: 5% vs −1%, p = 0.029). Conclusion:We demonstrated significant improvements in LV systolic, diastolic and endothelial function in patients treated with a dipeptidyl peptidase-4 inhibitor over 12 months. These beneficial effects may provide some reassurance regarding the cardiovascular safety of dipeptidyl peptidase-4 inhibitors.

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Dipeptidyl peptidase-4 inhibitor reduces infarct size and preserves cardiac function via mitochondrial protection in ischaemia–reperfusion rat heart

Abstract: DPP-4 inhibitor provides cardioprotection by reducing the infarct size and ameliorating cardiac dysfunction in I/R hearts by attenuating cardiac mitochondrial dysfunction and cardiomyocyte apoptosis.

Cited by 59 publications

References 49 publications

DPP-4 Inhibitor and Estrogen Share Similar Efficacy Against Cardiac Ischemic-Reperfusion Injury in Obese-Insulin Resistant and Estrogen-Deprived Female Rats

DPP-4 Inhibitor and Estrogen Share Similar Efficacy Against Cardiac Ischemic-Reperfusion Injury in Obese-Insulin Resistant and Estrogen-Deprived Female Rats

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

Effects of dipeptidyl peptidase-4 inhibitors on cardiac and endothelial function in type 2 diabetes mellitus: A pilot study

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