A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats

Nakajima, Yoshifumi; Ito, Shin; Asakura, Masanori; Min, Kyung‐Duk; Fu, Haiying; Imazu, Michinori; Hitsumoto, Tatsuro; Takahama, Hiroko; Shindo, Kazuhiro; Fukuda, Hiroki; Yamazaki, Satoru; Asanuma, Hiroshi; Kitakaze, Masafumi

doi:10.1016/j.yjmcc.2019.03.009

Cited by 13 publications

(7 citation statements)

References 41 publications

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“…In addition, a meta-analysis of 17,446 patients showed that the relative risk of prospectively adjudicated major adverse cardiac events (MACEs) in younger (< 65 years) patients with T2DM was significantly reduced by 37% in the vild group compared to the controls (McInnes et al, 2015;Evans et al, 2018). Other studies have shown that vild effectively improves cardiac function in different disease models, such as improving diastolic dysfunction in Dahl salt-sensitive hypertensive rats with HFpEF (Nakajima et al, 2019) and reducing T2DM-induced increase in post-MI acute mortality by restoring the autophagic response (Murase et al, 2015). However, little is known about the mechanisms of the cardioprotective effects of the drug.…”

Section: Introductionmentioning

confidence: 99%

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

Meng

Han

et al. 2021

Front. Pharmacol.

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Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms.Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy.Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor.Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.

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Section: Introductionmentioning

confidence: 99%

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

Meng

Han

et al. 2021

Front. Pharmacol.

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“…• again not assessed (Hirose et al, 2017). In 11-week-old Dahl salt-sensitive rats fed a high-salt diet (8.0% NaCl) to induce HFpEF, treatment with vildagliptin (provided in the drinking water to achieve 10 mg/kg/day) alleviated diastolic dysfunction as indicated by a decrease in LVEDP and an increase in the mitral E/A ratio (Nakajima et al, 2019). Nonetheless, Dahl saltsensitive rats with HFpEF exhibit decreases in body weight, and it remains undetermined whether such improvements in diastolic function would still be observed in the presence of underlying obesity/T2DM in this model.…”

Section: Dpp-4 Inhibitors and Diabetic Cardiomyopathy In Preclinical mentioning

confidence: 99%

“…Taken together, various DPP-4 inhibitors do appear to improve indices of diastolic function in various experimental models of either T2DM or heart failure ( Table 3), though it does appear that the impact on heart failure pathogenesis can be influenced by the underlying presence of obesity, insulin resistance and metabolic dysfunction. While reductions in cardiac fibrosis are consistently reported and may contribute to how DPP-4 inhibition improves diastolic function in preclinical studies (Lenski et al, 2011;Aroor et al, 2017;Hirose et al, 2017;Nakajima et al, 2019), other potential mechanisms at play include reductions in cardiac lipotoxicity due to reduced protein expression of the fatty acid transporter, CD36 (Lenski et al, 2011). Moreover, the linagliptin mediated improvement of diastolic function in high-fat/high sucrose/highfructose fed female C57BL/6J mice may involve restricting TRAF3 interacting protein-induced inflammation, a cytoplasmic adapter molecule that acts as an upstream regulator of NFκB (Aroor et al, 2017).…”

Section: Dpp-4 Inhibitors and Diabetic Cardiomyopathy In Preclinical mentioning

confidence: 99%

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy

et al. 2020

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Diabetic cardiomyopathy is more prevalent in people with type 2 diabetes mellitus (T2DM) than previously recognized, while often being characterized by diastolic dysfunction in the absence of systolic dysfunction. This likely contributes to why heart failure with preserved ejection fraction is enriched in people with T2DM vs. heart failure with reduced ejection fraction. Due to revised mandates from major health regulatory agencies, all therapies being developed for the treatment of T2DM must now undergo rigorous assessment of their cardiovascular risk profiles prior to approval. As such, we now have data from tens of thousands of subjects with T2DM demonstrating the impact of major therapies including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors on cardiovascular outcomes. Evidence to date suggests that both SGLT2 inhibitors and GLP-1R agonists improve cardiovascular outcomes, whereas DPP-4 inhibitors appear to be cardiovascular neutral, though evidence is lacking to determine the overall utility of these therapies on diastolic dysfunction or diabetic cardiomyopathy in subjects with T2DM. We herein will review the overall impact SLGT2 inhibitors, GLP-1R agonists, and DPP-4 inhibitors have on major parameters of diastolic function, while also highlighting the potential mechanisms of action responsible. A more complete understanding of how these therapies influence diastolic dysfunction will undoubtedly play a major role in how we manage cardiovascular disease in subjects with T2DM.

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“…Several studies have demonstrated that DPP4 inhibitors ameliorate LVH (Dos Santos et al, 2013;Arruda-Junior et al, 2016;Beraldo et al, 2019;Nakajima et al, 2019;Nam et al, 2019;Okabe et al, 2020), whereas upregulated activity and expression of heart DPP4 is associated with cardiac remodeling and dysfunction (Dos Santos et al, 2013;Arruda-Junior et al, 2016;Beraldo et al, 2019). The antihypertrophic effects of the DPP4 inhibitor teneligliptin have been recently unraveled in an experimental model of Ang II-induced hypertension (Okabe et al, 2020).…”

Section: Role Of Dipeptidyl Peptidase 4 (Dpp4)mentioning

confidence: 99%

“…The authors found that the administration of teneligliptin to C57BL/6J mice suppressed Ang II-induced NADPH oxidase 4 mRNA overexpression, ROS production, and attenuated LVH without affecting blood pressure (Okabe et al, 2020). DPP4 inhibition has also mitigated LV remodeling and dysfunction in other experimental models of hypertension, such as spontaneously hypertensive rats and Dahl salt-sensitive rats (Nakajima et al, 2019;Nam et al, 2019). However, in the FIGURE 1 | Putative mechanisms linking hypertension and COVID-19 severity.…”

Section: Role Of Dipeptidyl Peptidase 4 (Dpp4)mentioning

confidence: 99%

Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity

2020

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The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a public health crisis of major proportions. Advanced age, male gender, and the presence of comorbidities have emerged as risk factors for severe illness or death from COVID-19 in observation studies. Hypertension is one of the most common comorbidities in patients with COVID-19. Indeed, hypertension has been shown to be associated with increased risk for mortality, acute respiratory distress syndrome, need for intensive care unit admission, and disease progression in COVID-19 patients. However, up to the present time, the precise mechanisms of how hypertension may lead to the more severe manifestations of disease in patients with COVID-19 remains unknown. This review aims to present the biological plausibility linking hypertension and higher risk for COVID-19 severity. Emphasis is given to the role of the renin-angiotensin system and its inhibitors, given the crucial role that this system plays in both viral transmissibility and the pathophysiology of arterial hypertension. We also describe the importance of the immune system, which is dysregulated in hypertension and SARS-CoV-2 infection, and the potential involvement of the multifunctional enzyme dipeptidyl peptidase 4 (DPP4), that, in addition to the angiotensin-converting enzyme 2 (ACE2), may contribute to the SARS-CoV-2 entrance into target cells. The role of hemodynamic changes in hypertension that might aggravate myocardial injury in the setting of COVID-19, including endothelial dysfunction, arterial stiffness, and left ventricle hypertrophy, are also discussed.

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A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats

Cited by 13 publications

References 41 publications

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy

Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity

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