Mechanisms of [Ca2+]i Transient Decrease in Cardiomyopathy of <i>db</i>/<i>db</i> Type 2 Diabetic Mice

Pereira, Laëtitia; Matthes, Jan; Schuster, Iris; Valdivia, Héctor H.; Herzig, Stefan; Richard, Sylvain; Gómez, Ana M.

doi:10.2337/diabetes.55.03.06.db05-1284

Cited by 227 publications

(226 citation statements)

References 36 publications

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“…In agreement with previous findings with other experimental models of diabetes,43, 44, 45, 46, 47, 48 outward Kv currents and I CaL were significantly reduced in STZ myocytes (Figure 8A through 8D and Figure S7). These alterations may respectively promote and oppose prolongation of AP duration.…”

Section: Resultssupporting

confidence: 93%

“…Reductions of the K + channel subunit, Kv4.2, interacting protein KChIP2, and Ca 2+ channel α‐1C subunit have been proposed as molecular substrates for the decreased Kv currents and I CaL in myocytes from rodent models of diabetes 43, 45, 46, 47, 57, 59. Our electrophysiological data support the possibility that similar alterations occur in the STZ‐hyperglycemic mouse model employed here.…”

Section: Discussionsupporting

confidence: 85%

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Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Meo

Meste

Signore

et al. 2016

JAHA

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BackgroundDiabetes is associated with prolongation of the QT interval of the electrocardiogram and enhanced dispersion of ventricular repolarization, factors that, together with atherosclerosis and myocardial ischemia, may promote the occurrence of electrical disorders. Thus, we tested the possibility that alterations in transmembrane ionic currents reduce the repolarization reserve of myocytes, leading to action potential (AP) prolongation and enhanced beat‐to‐beat variability of repolarization.Methods and ResultsDiabetes was induced in mice with streptozotocin (STZ), and effects of hyperglycemia on electrical properties of whole heart and myocytes were studied with respect to an untreated control group (Ctrl) using electrocardiographic recordings in vivo, ex vivo perfused hearts, and single‐cell patch‐clamp analysis. Additionally, a newly developed algorithm was introduced to obtain detailed information of the impact of high glucose on AP profile. Compared to Ctrl, hyperglycemia in STZ‐treated animals was coupled with prolongation of the QT interval, enhanced temporal dispersion of electrical recovery, and susceptibility to ventricular arrhythmias, defects observed, in part, in the Akita mutant mouse model of type I diabetes. AP was prolonged and beat‐to‐beat variability of repolarization was enhanced in diabetic myocytes, with respect to Ctrl cells. Density of Kv K+ and L‐type Ca2+ currents were decreased in STZ myocytes, in comparison to cells from normoglycemic mice. Pharmacological reduction of Kv currents in Ctrl cells lengthened AP duration and increased temporal dispersion of repolarization, reiterating features identified in diabetic myocytes.ConclusionsReductions in the repolarizing K+ currents may contribute to electrical disturbances of the diabetic heart.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 85%

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Meo

Meste

Signore

et al. 2016

JAHA

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“…Using various techniques to evaluate cardiac contractile function, some investigators also found depressed contractility in murine models of diabetes, while others found only minimal or mildly decreased systolic function (5,(21)(22)(23)(24)(25). The wide variability in the magnitude of the reduction in fractional shortening or ejection fraction reported in these studies may be related to the duration of diabetes or age.…”

Section: Discussionmentioning

confidence: 72%

“…Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2)(3)(4)(5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force.…”

mentioning

confidence: 99%

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Jiang

et al. 2007

Diabetes

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OBJECTIVE-Contraction of cardiac myocytes is initiated byCa 2ϩ entry through the voltage-dependent L-type Ca 2ϩ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling. RESEARCH DESIGN AND METHODS-We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2 Akita mutation versus nondiabetic littermates.RESULTS-Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased L-type Ca 2ϩ current (I Ca,L ) density in myocytes compared with control nondiabetic littermates. The lower I Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P 3 stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P 3 infusion eliminated only the difference in voltage dependence of steady-state inactivation of I Ca,L .CONCLUSIONS-Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca 2ϩ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility. Diabetes 56:2780-2789, 2007 C ardiac complications are an important cause of morbidity and mortality in type 1 diabetic patients. This is partly due to the presence of hypertension and coronary artery disease, which are commonly associated with diabetes. Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2-5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force. However, the molecular mechanism that underlies the LTCC defect in diabetic myocytes is unclear.Class I phosphatidylinositol (PI) 3-kinases preferentially phosphorylate PI 4,5-bisphosphate [PI(4,5)P 2 ] to form phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] in vivo and exhibit substantial activation in response to stimulation with insulin or other hormones. Studies in neuron...

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“…Studies in humans and animal models of DM have demonstrated abnormal myofilament function (37) and impaired excitation-contraction coupling (38), which may depress myocardial function. Because diabetes is associated with a differential expression of myosin isozymes in the heart (39, 40), we utilized a proteomic approach with 2D-DIGE and MALDI-TOF/TOF-tandem mass spectrometry and identified four cytoskeletal/contractile proteins in db/db mouse hearts that were significantly altered after chronic treatment with rapamycin (Table 1).…”

Section: D-dige Spotmentioning

confidence: 99%

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Das

Durrant

Koka

et al. 2014

Journal of Biological Chemistry

134

122

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Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to diabetic complications. Results: mTOR inhibitor, rapamycin, improves metabolic status and cardiac function, attenuates oxidative stress, and alters antioxidant and contractile protein expression in type 2 diabetic mice. Conclusion: Rapamycin may provide metabolic and cardiac benefits in diabetic mice. Significance: mTOR inhibition may be an attractive novel therapeutic strategy for diabetes-related complications.

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Mechanisms of [Ca2+]i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice

Cited by 227 publications

References 36 publications

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

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