Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Semple, David; Bhandari, Sunil; Seymour, Anne-Marie L.

doi:10.1152/ajprenal.00048.2012

Cited by 10 publications

(6 citation statements)

References 93 publications

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“…[32][33][34] Anemia, increased afterload due to aortic stiffness and hypertension, increased oxidative stress, and insulin resistance are other important contributors to the development of UC. 25,35,36 Another factor is hyperphosphatemia; in rats with subtotal nephrectomy, a high-phosphorus diet increased the severity of interstitial fibrosis and microvascular disease. 37 In patients free of known cardiovascular disease, dietary phosphorus was associated with a greater left ventricular mass.…”

Section: Discussionmentioning

confidence: 99%

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

Kramann¹,

Erpenbeck²,

Schneider

et al. 2014

Journal of the American Society of Nephrology

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Cardiovascular mortality is high in ESRD, partly driven by sudden cardiac death and recurrent heart failure due to uremic cardiomyopathy. We investigated whether speckle-tracking echocardiography is superior to routine echocardiography in early detection of uremic cardiomyopathy in animal models and whether it predicts cardiovascular mortality in patients undergoing dialysis. Using speckle-tracking echocardiography in two rat models of uremic cardiomyopathy soon (4-6 weeks) after induction of kidney disease, we observed that global radial and circumferential strain parameters decreased significantly in both models compared with controls, whereas standard echocardiographic readouts, including fractional shortening and cardiac output, remained unchanged. Furthermore, strain parameters showed better correlations with histologic hallmarks of uremic cardiomyopathy. We then assessed echocardiographic and clinical characteristics in 171 dialysis patients. During the 2.5-year follow-up period, ejection fraction and various strain parameters were significant risk factors for cardiovascular mortality (primary end point) in a multivariate Cox model (ejection fraction hazard ratio [HR], 0.97 [95% confidence interval (95% CI), 0.95 to 0.99; P=0.012]; peak global longitudinal strain HR, 1.17 [95% CI, 1.07 to 1.28; P,0.001]; peak systolic and late diastolic longitudinal strain rates HRs, 4.7 [95% CI, 1.23 to 17.64; P=0.023] and 0.25 [95% CI, 0.08 to 0.79; P=0.02], respectively). Multivariate Cox regression analysis revealed circumferential early diastolic strain rate, among others, as an independent risk factor for all-cause mortality (secondary end point; HR, 0.43; 95% CI, 0.25 to 0.74; P=0.002). Together, these data support speckle tracking as a postprocessing echocardiographic technique to detect uremic cardiomyopathy and predict cardiovascular mortality in ESRD.

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Section: Discussionmentioning

confidence: 99%

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

Kramann¹,

Erpenbeck²,

Schneider

et al. 2014

Journal of the American Society of Nephrology

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“…Earlier animal studies consistently showed that CKD enlarges myocardial infarct size after ischemia/reperfusion [5,8,9], and significant impairment of mitochondrial functions by uremia was recently reported [36]. On the other hand, myocardial responses to protection afforded by ischemic or pharmacological preconditioning were reported to be preserved in some, but not all, rat models of CKD [5,9,32]. However, the impact of CKD on pro-survival signal pathways in cardiomyocytes at the time of reperfusion has not been fully characterized, and the Toshiyuki Tobisawa and Toshiyuki Yano contributed equally to this work.…”

Section: Introductionmentioning

confidence: 95%

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

et al. 2017

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Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3β was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

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“…The cardioprotective effects of insulin were here studied through a range of cardiac preparations. Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection [25] . Cells treated with insulin were found to be to be less vulnerable to IR-injury than control cells [26] .…”

Section: Discussionmentioning

confidence: 99%

Insulin Protects Apoptotic Cardiomyocytes from Hypoxia/Reoxygenation Injury through the Sphingosine Kinase/Sphingosine 1-Phosphate Axis

Che

et al. 2013

PLoS ONE

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ObjectiveExperimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective, but the mechanisms underlying this effect are still unknown. In this study, the ability of insulin to protect apoptotic cardiomyocytes from hypoxia/reoxygenation injury using the sphingosine kinase/sphingosine 1-phosphate axis was investigated.Methods and ResultsRat cardiomyocytes were isolated and subjected to hypoxia and reoxygenation. [γ-32P] ATP was used to assess sphingosine kinase activity. Insulin was found to increase sphingosine kinase activity. Immunocytochemistry and Western blot analysis showed changes in the subcellular location of sphingosine kinase 1 from cytosol to the membrane in cardiomyocytes. Insulin caused cardiomyocytes to accumulate of S1P in a dose-dependent manner. FRET efficiency showed that insulin also transactivates the S1P1 receptor. TUNEL staining showed that administration of insulin during reoxygenation could to reduce the rate of reoxygenation-induced apoptosis, which is a requirement for SphK 1 activity. It also reduced the rate of activation of the S1P receptor and inhibited hypoxia/reoxygenation-induced cell death in cardiomyocytes.ConclusionThe sphingosine kinase 1/sphingosine 1-phosphate/S1P receptor axis is one pathway through which insulin protects rat cardiomyocytes from apoptosis induced by hypoxia/reoxygenation injury.

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Uremic cardiomyopathy is characterized by loss of the cardioprotective effects of insulin

Cited by 10 publications

References 93 publications

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

Insulin Protects Apoptotic Cardiomyocytes from Hypoxia/Reoxygenation Injury through the Sphingosine Kinase/Sphingosine 1-Phosphate Axis

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