Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature

Shida, Takuya; Nozawa, Takashi; Sobajima, Mitsuo; Ihori, Hiroyuki; Matsuki, Akira; Inoue, Hiroshi

doi:10.1007/s00380-013-0402-6

Cited by 28 publications

(26 citation statements)

References 51 publications

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“…The myocardial blood flow response to increased demand is a strong independent predictor of heart failure progression [28]. Improvement in coronary microvasculature by reducing myocardial oxidative Tumor necrosis factor-α, pg/mL 1.5 ± 1.0 1.5 ± 0.7 0.30 stress and endothelial nitric oxide synthase upregulation has been reported to ameliorate LV dysfunction in vivo model [29]. On the basis of the results of this study, we speculated that improvement of endothelial dysfunction led to an increase in coronary blood flow of the epicardial and intramyocardial microcirculation and a decrease in microvascular dysfunction that ultimately contributed to the progression of LV dysfunction.…”

Section: Discussionmentioning

confidence: 98%

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

et al. 2015

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Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-D-glucitol levels increased (9.6 ± 7.2 μg/mL to 13.5 ± 8.7 μg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e') ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e' ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.

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Section: Discussionmentioning

confidence: 98%

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

et al. 2015

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“…Substances with antioxidant activity such as vitamin E or fluvastatin, reduce myocardial NADPH oxidase subunits and oxidized glutathione which consequently improve LV function in DCM (Hamblin et al 2007;Shida et al 2014). Similarly, ATOR decreases DM-induced cardiac lipid peroxide levels, which may be attributed to its pleotropic inhibitory effect on GTP-binding proteins, RAC1 and RHOA (Van Linthout et al 2007).…”

Section: Discussionmentioning

confidence: 95%

“…Its prevalence ranges roughly from 14.5 to 30 % in longstanding type 1 DM (Konduracka et al 2013;Shida et al 2014). Moreover, 75 % of unexplained dilated CM cases were found to be diabetic (Tarquini et al 2011).…”

Section: Introductionmentioning

confidence: 98%

Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress

Abdel-Hamid

Firgany

2015

J Mol Hist

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Diabetic hazard on the myocardium is a complication of diabetes that intensifies its morbidity and increases its mortality. Therefore, alleviation of diabetic cardiomyopathy (DCM) by a reliable drug remains a matter of interest in experimental research. The aim of this study was to explore the structural alterations in the myocardium induced by atorvastatin (ATOR) in DCM, induced by streptozotocin (STZ), along with the associated changes occurring in apoptosis and oxidative stress markers. Thirty-two rats were divided into four groups; group A (control), group B (non-diabetic, received ATOR, orally, 50 mg/kg daily), group C (DCM, received STZ 70 mg/kg, single i.p. injection) and group D (DCM + ATOR). After 6 weeks, left ventricle (LV) specimens were prepared for histological and immunohistochemical study by hematoxlyin and eosin, Masson`s trichrome, anti-cleaved caspase-3 stains as well as for assays of oxidative stress markers. All data were measured morphometrically and statistically analyzed. The DCM group showed disorganization of the cardiomyocytes, interstitial edema, numerous fibroblasts, significant increases in the collagen volume fraction (p < 0.001), cleaved caspase-3 expression % area (p < 0.001) and, malondialdehyde in blood (p < 0.001), in LV (p < 0.05) compared with DCM + ATOR group. The latter has LV wall thickness, relative heart weight and antioxidant activities nearly similar to the control, independent from ATOR lipid-lowering effect. Therefore, ATOR can preserve myocardial structure in DCM nearly similar to normal. This may be achieved by suppressing apoptosis that parallels the correction of the antioxidant markers, which can be considered as non-lipid lowering benefit of statins.

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“…Endothelial cells appear to be the first cell type injured by ROS generated during H/R [7]. Reduction of oxidative stress improves coronary microvasculature [22]. In the previous study, HGF function in a unique fashion in that it does not employ ROS as its own downstream signaling molecules, but rather inhibits one of the cellular machineries responsible for ROS generation, such as Rac-1 [23].…”

Section: Discussionmentioning

confidence: 96%

Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells

Zhang

Chen

2014

Heart Vessels

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Hypoxia/reoxygenation (H/R) is one of the cellular stresses in pathological conditions, such as myocardial infarction, stroke and organ transplantation. Oxidative stress caused by reactive oxygen species (ROS) is a crucial element of H/R injury in vascular endothelial cells (ECs). Xanthine oxidase (XO) has been recognized to contribute to H/R injury. Of note, xanthine oxidoreductase is synthesized as xanthine dehydrogenase (XDH) and needs to be converted to XO to become a source of superoxide. Hepatocyte growth factor (HGF) has been found to protect ECs against H/R injury. The relation, however, between HGF and XO in ECs under H/R conditions remains to be determined. Primary cultured rat cardiac microvascular endothelial cells (CMECs) were exposed to 4 h of hypoxia and followed by 1 h of reoxygenation. Generation of ROS and cytosolic Ca2+ concentration was measured by flow cytometry qualification of DCFHDA and fluo-3 AM staining cells, respectively. XDH mRNA was qualified by qRT-PCR analysis. XO activity was determined by colorimetric assay and XO protein levels were determined by Western blot. Cell apoptosis was assessed by caspase-3 activity and Annexin V/PI staining. After H/R, cellular ROS production significantly increased. Both XO activity and XO protein increased after H/R. Cellular ROS elevation was inhibited by allopurinol (a potent XO inhibitor), indicting XO accounting for the generation of ROS after H/R. In addition, XDH mRNA increased after H/R, indicating a de novo XDH synthesis, which needs to be converted to XO to become a source of superoxide. Pretreatment of HGF inhibited the elevation of XO activity and XO protein level after H/R; however, HGF has no effect on the increase of XDH mRNA. We also find an increase of the cytosolic Ca2+ in CMECs after H/R. BAPTA-AM, a cell-permeable Ca2+ chelator, prevented the increase of XO activity and XO protein levels, implicating the elevated cytosolic Ca2+ concentration involvement in XO conversion and XO activation. HGF inhibited the elevation of cytosolic Ca2+ concentration in CMECs after H/R. Furthermore, HGF ameliorated H/R-induced CMECs apoptosis. These findings suggest a novel mechanism whereby HGF inhibited XO-generated ROS production after H/R treatment. H/R induces a de novo synthesis of XDH, the XO precursor. In addition, H/R increases cytosolic Ca2+ concentration and promotes a Ca2+ -involved XO conversion and XO activation. HGF has no effect on the increase of XDH mRNA; however, HGF inhibited the elevation of XO protein level and XO activity after H/R in the post-transcriptional level primarily by inhibiting the increase of cytosolic Ca2+ concentration. HGF protects CMECs from H/R-induced apoptosis by inhibiting the elevation of XO protein level and XO activity.

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Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature

Cited by 28 publications

References 51 publications

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress

Hepatocyte growth factor suppresses hypoxia/reoxygenation-induced XO activation in cardiac microvascular endothelial cells

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