Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats

Miyoshi, Toru; Nakamura, Kazufumi; Yoshida, Masashi; Miura, Daiji; Oe, Hiroki; Akagi, Satoshi; Sugiyama, Hiroki; Akazawa, Kaoru; Yonezawa, Tomoko; Wada, Jun; Ito, Hiroshi

doi:10.1186/1475-2840-13-43

Cited by 56 publications

(39 citation statements)

References 47 publications

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“…However, vildagliptin, metformin, and combined metformin and vildagliptin also reduced LDL cholesterol level without any changes in blood pressure. This finding consistent with previous reports in the heart failure model in which vildagliptin did not change blood pressure in rats with cardiac hypertrophy (Miyoshi et al 2014), and metformin did not affect blood pressure and flow-mediated vasodilation in insulin-resistant patients with chronic HF (Wong et al 2012). These data suggest that a reduction of LDL cholesterol level along with lower angiotensin II is necessary to reduce blood pressure in obese-insulinresistant rats with chronic MI.…”

Section: Discussionsupporting

confidence: 92%

“…It has been shown to preserve LV function and reduce the infarct size in cardiac I/R injury (Chinda et al 2013, Apaijai et al 2014. Moreover, vildagliptin reduced myocyte hypertrophy and perivascular and cardiac fibrosis in isoproterenol (Miyoshi et al 2014), and transverse aortic constriction-induced heart failure (Takahashi et al 2013). However, inconsistent findings exist as reported by Yin and colleagues who found that vildagliptin did not reverse LV remodeling in post-MI-induced heart failure rats (Yin et al 2011).…”

Section: Introductionmentioning

confidence: 98%

“…In the heart, vildagliptin has been shown to exert beneficial effects in various models , Miyoshi et al 2014. It has been shown to preserve LV function and reduce the infarct size in cardiac I/R injury (Chinda et al 2013, Apaijai et al 2014.…”

Section: Introductionmentioning

confidence: 99%

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Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction

Apaijai

Inthachai

Lekawanvijit

et al. 2016

Journal of Endocrinology

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Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Obese-insulin resistance increases risks of MI and heart failure. Although dipeptidyl peptidase-4 (DPP4) inhibitor is known to exert cardioprotection, its effects on adverse remodeling after MI in obese-insulin-resistant rats are unclear. We hypothesized that DPP4 inhibitor reduces adverse left ventricular (LV) remodeling and LV dysfunction in obese-insulin-resistant rats with MI. Rats were fed either normal diet (ND) or highfat diet (HFD) for 12 weeks to induce obese-insulin resistance, followed by left anterior descending coronary artery ligation to induce MI. Then, rats in each dietary group were divided into five subgroups to receive vehicle, enalapril (10 mg/kg/day), metformin (30 mg/kg/day), DPP4 inhibitor vildagliptin (3 mg/kg/day), or combined metformin and vildagliptin for 8 weeks. Heart rate variability (HRV), LV function, pathological and biochemical studies for LV remodeling, and cardiomyocyte apoptosis were determined. Obese-insulin-resistant rats had severe insulin resistance and LV dysfunction. HFD rats had a higher mortality rate than ND rats, and all treatments reduced the mortality rate in obese-insulin-resistant rats. Although all drugs improved insulin resistance, HRV, LV function as well as reduced cardiac hypertrophy and fibrosis, vildagliptin effectively reduced cardiomyocyte cross-sectional areas more than enalapril and was related to markedly decreased ERK1/2 phosphorylation. In ND rats with MI, metformin neither improved LV ejection fraction nor reduced cardiac fibrosis. The infarct size and transforming growth factor-β expression were not different among groups. In obese-insulin-resistant rats with chronic MI, DPP4 inhibitor vildagliptin exerts better cardioprotection than enalapril in attenuating adverse LV remodeling.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

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Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction

Apaijai

Inthachai

Lekawanvijit

et al. 2016

Journal of Endocrinology

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“…Considerable evidence also links the attenuation of DPP4 activity to improvement in ventricular function and reduced systemic and cardiac inflammation (6,(27)(28)(29). Hence, we were surprised to detect increased cardiac expression of mRNA transcripts encoding multiple effectors of the immune response in normoglycemic mice with reduced DPP4 activity.…”

Section: Discussionmentioning

confidence: 93%

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat–Fed Diabetic Mice

et al. 2015

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Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of DPP4 inhibitor–treated subjects with diabetes. We evaluated cardiovascular function in young euglycemic Dpp4−/− mice and in older, high fat–fed, diabetic C57BL/6J mice treated with either the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide or the highly selective DPP4 inhibitor MK-0626. We assessed glucose metabolism, ventricular function and remodeling, and cardiac gene expression profiles linked to inflammation and fibrosis after transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4−/− mice exhibited a cardioprotective response after TAC surgery or doxorubicin administration, with reduced fibrosis; however, cardiac mRNA analysis revealed increased expression of inflammation-related transcripts. Older, diabetic, high fat–fed mice treated with the GLP-1R agonist liraglutide exhibited preservation of cardiac function. In contrast, diabetic mice treated with MK-0626 exhibited modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins controlling inflammation and cardiac fibrosis. These findings provide a model for the analysis of mechanisms linking fibrosis, inflammation, and impaired ventricular function to DPP4 inhibition in preclinical studies.

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“…These effects were accompanied by the amelioration of perivascular fibrosis and expression of genes associated with glucose uptake (GLUT4) and inflammation (TNF α and IL-6) [23]. …”

Section: Cardiovascular Effects Of Dpp-4 Inhibitormentioning

confidence: 99%

The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

Kim

Lee

2014

BioMed Research International

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A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

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Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats

Cited by 56 publications

References 47 publications

Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction

Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat–Fed Diabetic Mice

The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

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