67 research outputs found

    Myocyte [Na\u3csup\u3e+\u3c/sup\u3e]\u3csub\u3ei\u3c/sub\u3e Dysregulation in Heart Failure and Diabetic Cardiomyopathy

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    By controlling the function of various sarcolemmal and mitochondrial ion transporters, intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, electrical activity, the matching of energy supply and demand, and oxidative stress in cardiac myocytes. Thus, maintenance of myocyte Na+ homeostasis is vital for preserving the electrical and contractile activity of the heart. [Na+]i is set by the balance between the passive Na+ entry through numerous pathways and the pumping of Na+ out of the cell by the Na+/K+-ATPase. This equilibrium is perturbed in heart failure, resulting in higher [Na+]i. More recent studies have revealed that [Na+]i is also increased in myocytes from diabetic hearts. Elevated [Na+]i causes oxidative stress and augments the sarcoplasmic reticulum Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. This mini-review compares and contrasts the alterations in Na+ extrusion and/or Na+ uptake that underlie the [Na+]i increase in heart failure and diabetes, with a particular emphasis on the emerging role of Na+ - glucose cotransporters in the diabetic heart

    Amylin and Diabetic Cardiomyopathy – Amylin-Induced Sarcolemmal Ca\u3csup\u3e2+\u3c/sup\u3e Leak Is Independent of Diabetic Remodeling of Myocardium

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    Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human amylin. Whether deposition of amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used amylin knockout (AKO) mice intravenously infused with either human amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent amylin to test the hypothesis that aggregated amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human, but not rodent amylin, showed amylin deposits in the myocardium. Cardiac amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human amylin while no significant changes occurred in either females injected with human amylin or in rat amylin-infused mice. In isolated cardiac myocytes, the amylin receptor antagonist AC-187 did not effectively block the interaction of amylin with the sarcolemma. In conclusion, circulating aggregated amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium

    Intracellular Na\u3csup\u3e+\u3c/sup\u3e Concentration ([Na\u3csup\u3e+\u3c/sup\u3e]i) Is Elevated in Diabetic Hearts Due to Enhanced Na\u3csup\u3e+\u3c/sup\u3e–Glucose Cotransport

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    BACKGROUND: Intracellular Na+ concentration ([Na+]i) regulates Ca2+ cycling, contractility, metabolism, and electrical stability of the heart. [Na+]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na+]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na+-glucose cotransporter. METHODS AND RESULTS: To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na+-glucose cotransporter expression in failing hearts from T2D patients compared with nondiabetic persons (by 73±13%) and in HIP rat hearts versus wild-type (WT) littermates (by 61±8%). [Na+]i was elevated in HIP rat myocytes both at rest (14.7±0.9 versus 11.4±0.7 mmol/L in WT) and during electrical stimulation (17.3±0.8 versus 15.0±0.7 mmol/L); however, the Na+/K+-pump function was similar in HIP and WT cells, suggesting that higher [Na+]i is due to enhanced Na+ entry in diabetic hearts. Indeed, Na+ influx was significantly larger in myocytes from HIP versus WT rats (1.77±0.11 versus 1.29±0.06 mmol/L per minute). Na+-glucose cotransporter inhibition with phlorizin or glucose-free solution greatly reduced Na+ influx in HIP myocytes (to 1.20±0.16 mmol/L per minute), whereas it had no effect in WT cells. Phlorizin also significantly decreased glucose uptake in HIP myocytes (by 33±9%) but not in WT, indicating an increased reliance on the Na+-glucose cotransporter for glucose uptake in T2D hearts. CONCLUSIONS: Myocyte Na+-glucose cotransport is enhanced in T2D, which increases Na+ influx and causes Na+ overload. Higher [Na+]i may contribute to arrhythmogenesis and oxidative stress in diabetic hearts

    Gestational Diabetes Triggers Postpartum Cardiac Hypertrophy via Activation of Calcineurin/NFAT Signaling

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    Population-based studies identified an association between a prior pregnancy complicated by gestational diabetes mellitus (GDM) and cardiac hypertrophy and dysfunction later in life. It is however unclear whether GDM initiates this phenotype and what are the underlying mechanisms. We addressed these questions by using female rats that express human amylin (HIP rats) as a GDM model and their wild-type (WT) littermates as the normal pregnancy model. Pregnant and two months postpartum HIP females had increased left-ventricular mass and wall thickness compared to non-pregnant HIP females, which indicates the presence of concentric hypertrophy. These parameters were unchanged in WT females during both pregnancy and postpartum periods. Hypertrophic Ca2+-dependent calcineurin/NFAT signaling was stimulated two months after giving birth in HIP females but not in the WT. In contrast, the CaMKII/HDAC hypertrophy pathway was active immediately after giving birth and returned to the baseline by two months postpartum in both WT and HIP females. Myocytes from two months postpartum HIP females exhibited slower Ca2+ transient relaxation and higher diastolic Ca2+ levels, which may explain calcineurin activation. No such effects occurred in the WT. These results suggest that a GDM-complicated pregnancy accelerates the development of pathological cardiac remodeling likely through activation of calcineurin/NFAT signaling

    Na/K Pump-Induced [Na]i Gradients in Rat Ventricular Myocytes Measured with Two-Photon Microscopy

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    AbstractVia the Na/Ca and Na/H exchange, intracellular Na concentration ([Na]i) is important in regulating cardiac Ca and contractility. Functional data suggest that [Na]i might be heterogeneous in myocytes that are not in steady state, but little direct spatial information is available. Here we used two-photon microscopy of SBFI to spatially resolve [Na]i in rat ventricular myocytes. In vivo calibration yielded an apparent Kd of 27±2mM Na. Similar resting [Na]i was found using two-photon or single-photon ratiometric measurements with SBFI (10.8±0.7 vs. 11.1±0.7mM). To assess longitudinal [Na]i gradients, Na/K pumps were blocked at one end of the myocyte (locally pipette-applied K-free extracellular solution) and active in the rest of the cell. This led to a marked increase in [Na]i at sites downstream of the pipette (where Na enters the myocyte and Na/K pumps are blocked). [Na]i rise was smaller at upstream sites. This resulted in sustained [Na]i gradients (up to ∼17 mM/120μm cell length). This implies that Na diffusion in cardiac myocytes is slow with respect to trans-sarcolemmal Na transport rates, although the mechanisms responsible are unclear. A simple diffusion model indicated that such gradients require a Na diffusion coefficient of 10–12μm2/s, significantly lower than in aqueous solutions

    Cardioprotection by Controlling Hyperamylinemia in a Humanized Diabetic Rat Model

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    BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart. METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca2+ dysregulation. In time, HIP rats developed cardiac hypertrophy and left-ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left-ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin-induced cardiac oxidative stress and Ca2+ dysregulation. CONCLUSIONS: The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin-mediated cardiotoxicity

    The association of circulating amylin with β-amyloid in familial Alzheimer's disease.

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    Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD). Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding. Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms
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